Isotopically enriched arylsulfonamide CCR3 antagonists

ABSTRACT

Provided herein are isotopically enriched arylsulfonamides, for example, of Formula I, that are useful for modulating CCR3 activity, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a CCR3-mediated disease, disorder, or condition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/020,597, filed Sep. 6, 2013, which claims the benefit of U.S.Provisional Patent Application Ser. No. 61/698,390, filed Sep. 7, 2012,the disclosure of each of which is incorporated herein by reference inits entirety.

FIELD

Provided herein are isotopically enriched arylsulfonamides that areuseful for modulating CCR3 activity, and pharmaceutical compositionsthereof. Also provided herein are methods of their use for treating,preventing, or ameliorating one or more symptoms of a CCR3-mediateddisease, disorder, or condition.

BACKGROUND

CC chemokine receptor 3 (CCR3) is a seven-transmembrane Gprotein-coupled receptor, which binds to a variety of CC chemokines,including eotaxin (CCL11), eotaxin-2 (CCL24), eotaxin-3 (CCL26), MCP-3(CCL7), MCP-4 (CCL13), and RANTES (CCL5). CCR3 is known to be a majorchemokine receptor expressed on allergic inflammatory cells, includingeosinophils, basophils, mast cells, and T helper 2-type CD4⁺ cells(Combadiere et al., J. Biol. Chem. 1995, 270, 16491-16494; Post et al.,J. Immunol. 1995, 155, 5299-5305). Eosinophils have been implicated inthe pathogenesis of a number of allergic diseases, such as bronchialasthma (Durham and Kay, Clin. Allergy 1985, 15, 411-418; Kroegel et al.,J. Allergy Clin. Immunol. 1994, 93, 725-734), allergic rhinitis (Durham,Clin. Exp. Allergy 1998, 28 Suppl. 2, 11-16), atopic dermatitis (Leung,J. Allergy Clin. Immunol. 1999, 104, S99-108), and eosinophilicgastroenteritis (Bischoff et al., Am. J. Gastro. 1999, 94, 3521-3529).It has been demonstrated that activated eosinophils release major basicprotein (MBP), which blocks inhibitory M2 muscarinic receptors (M2Rs) onnerves, increasing acetylcholine release and potentiating vagallymediated bronchoconstriction (Evans et al., J. Clin. Invest. 1997, 100,2254-2262).

Numerous reports indicate that CCR3 plays important roles in allergicconditions. For example, it has been reported that, in both atopic andnonatopic asthma patients, there are increases in both mRNA and proteinlevels of CCR3 and its ligands, eotaxin, eotaxin-2, RANTES, and MCP-4(Ying et al., J. Immunol. 1999, 99, 6321-6329). It has also beendemonstrated that CCR3 gene deletion impairs eosinophil recruitment inan acute model of experimental asthma (Humbles et al., Proc. Natl. Acad.Sci. USA 2002, 99, 1479-1484; Ma et al., J. Clin. Invest. 2002, 109,621-628; Pope et al., J. Immunol. 2005, 175, 5341-5350; Fulkerson etal., Proc. Natl. Acad. Sci. USA 2006, 103, 16418-16423). Furthermore,studies have shown that CCR3 antagonists, such as anti-CCR3 monoclonalantibodies, block binding of CCR3-ligands to either CCR3 transfectantsor eosinophils, thus blocking chemotaxis of eosinophils induced by CCchemokines, such as eotaxin, RANTES, or MCP-3 (Heath et al., J. Clin.Invest. 1997, 99, 178-184; Grimaldi et al., J. Leukocyte Biol. 1999, 65,846-853; Justice et al., Am. J. Physiol. 2003, 284, L168-L178).Therefore, CCR3 antagonists are potentially useful for the treatment ofinflammatory diseases, such as allergic rhinitis and allergic asthma. Inaddition, CCR3 antagonists are also potentially useful for blockinginfection of CCR3 expressing cells by certain microorganisms, such asHIV, as CCR3 is known to be an entry co-receptor for certainmicroorganisms.

SUMMARY OF THE DISCLOSURE

Provided herein is an arylsulfonamide of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof;wherein:

R¹, R², R³, R⁴, R⁵, and R⁸ are each independently (a) hydrogen,deuterium, halo, cyano, nitro, or guanidine; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R⁶, R⁷, and R⁹ are each independently (a) hydrogen or deuterium;

R¹⁰ is (a) hydrogen; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c);

R¹¹ is (a) deuterium, halo, cyano, nitro, oxo, or guanidine; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a) S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen,deuterium, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or each pair of R^(1b) andR^(1c) together with the N atom to which they are attached independentlyform heteroaryl or heterocyclyl;

X is O or S;

m is an integer of 0, 1, 2, or 3;

n is an integer of 1, 2, or 3; and

p is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14;

wherein the arylsulfonamide is isotopically enriched;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,heterocyclyl, and heteroaryl is optionally substituted with one or moresubstituents Q, where each Q is independently selected from (a)deuterium, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a); and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen or deuterium; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ^(a); or (iii) each pair of R^(b) and R^(e) together with the N atom towhich they are attached form heterocyclyl, optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ^(a);

-   -   wherein each Q^(a) is independently selected from the group        consisting of (a) deuterium, cyano, halo, and nitro; (b) C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,        C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^(e),        —C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e),        —OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g),        —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),        —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),        —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),        —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),        —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),        —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),        —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e),        R^(f), R^(g), and R^(h) is independently (i) hydrogen or        deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇        cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or        heterocyclyl; or (iii) each pair of R^(f) and R^(g) together        with the N atom to which they are attached form heterocyclyl.

Also provided herein are pharmaceutical compositions comprising acompound disclosed herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; and one or more pharmaceutically acceptable carriers.

Additionally provided herein is a method for treating, preventing, orameliorating one or more symptoms of a CCR3-mediated disease, disorder,or condition in a subject, comprising administering to the subject atherapeutically effective amount of a compound disclosed herein, e.g., acompound of Formula I, an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, a tautomer, or a mixture of two ormore tautomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof.

Furthermore, provided herein is a method for modulating CCR3 activity,comprising contacting a CCR3 with a therapeutically effective amount ofa compound disclosed herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disease, disorder, or condition, or one ormore of the symptoms associated with the disease, disorder, orcondition; or alleviating or eradicating the cause(s) of the disease,disorder, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disease, disorder,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disease, disorder, or condition; or reducing a subject'srisk of acquiring a disease, disorder, or condition.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the disease, disorder, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit a biological or medical responseof a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,tissue, system, animal, or human, which is being sought by a researcher,veterinarian, medical doctor, or clinician.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a disease, disorder,or condition. As used herein, “active ingredient” and “active substance”may be an optically active isomer of a compound described herein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a disease, disorder, or condition.

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical, wherein the alkyl is optionally be substituted withone or more substituents Q as described herein. For example, C₁₋₆ alkylrefers to a linear saturated monovalent hydrocarbon radical of 1 to 6carbon atoms or a branched saturated monovalent hydrocarbon radical of 3to 6 carbon atoms. In certain embodiments, the alkyl is a linearsaturated monovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to15 (C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,C₁₋₆ alkyl, including linear C₁₋₆ and branched C₃₋₆ alkyl, is alsoreferred as “lower alkyl.” Examples of alkyl groups include, but are notlimited to, methyl, ethyl, propyl (including all isomeric forms),n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl,isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), andhexyl (including all isomeric forms).

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five, inanother embodiment, one, carbon-carbon double bond(s). In certainembodiments, the alkenyl is optionally substituted with one or moresubstituents Q as described herein. The term “alkenyl” embraces radicalshaving a “cis” or “trans” configuration or a mixture thereof, oralternatively, a “Z” or “E” configuration or a mixture thereof, asappreciated by those of ordinary skill in the art. For example, C₂₋₆alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbonradical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is alinear monovalent hydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15(C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branchedmonovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groupsinclude, but are not limited to, ethenyl, propen-1-yl, propen-2-yl,allyl, butenyl, and 4-methylbutenyl.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five, inanother embodiment, one, carbon-carbon triple bond(s). In certainembodiments, the alkynyl is optionally substituted with one or moresubstituents Q as described herein. For example, C₂₋₆ alkynyl refers toa linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbonatoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms. In certain embodiments, the alkynyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkynyl groupsinclude, but are not limited to, ethynyl (—C≡CH), propynyl (includingall isomeric forms, e.g., 1-propynyl (—C≡CCH₃) and propargyl(—CH₂C≡CH)), butynyl (including all isomeric forms, e.g., 1-butyn-1-yland 2-butyn-1-yl), pentynyl (including all isomeric forms, e.g.,1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including allisomeric forms, e.g., 1-hexyn-1-yl).

The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical,which is saturated or unsaturated, but non-aromatic. In certainembodiments, the cycloalkyl is bridged. In certain embodiments, thecycloalkyl is a fused ring group, e.g., a fused bicyclic group. Incertain embodiments, the cycloalkyl is optionally substituted with oneor more substituents Q as described herein. In certain embodiments, thecycloalkyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ringsystem. In certain embodiments, the cycloalkyl is a cyclic monovalenthydrocarbon radical having from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅),from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms. Examples ofcycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.

The term “aryl” refers to a monovalent monocyclic aromatic group and/ormonovalent polycyclic aromatic group that contain at least one aromaticcarbon ring. In certain embodiments, the aryl is a monovalent aromaticgroup having from 6 to 20 (C₆₋₂₀), from 6 to 15 (C₆₋₁₅), or from 6 to 10(C₆₋₁₀) ring atoms. Examples of aryl groups include, but are not limitedto, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl,pyrenyl, biphenyl, and terphenyl. In certain embodiments, the aryl is abicyclic or tricyclic carbon ring, where one of the rings is aromaticand the others of which may be saturated, partially unsaturated, oraromatic, for example, dihydronaphthyl, indenyl, indanyl, ortetrahydronaphthyl (tetralinyl). In certain embodiments, the aryl isoptionally substituted with one or more substituents Q as describedherein.

The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl groupsubstituted with one or more aryl groups. In certain embodiments, thearyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system.In certain embodiments, the aralkyl is a monovalent alkyl group havingfrom 7 to 30 (C₇₋₃₀), from 7 to 20 (C₇₋₂₀), or from 7 to 16 (C₇₋₁₆)carbon atoms. Examples of aralkyl groups include, but are not limitedto, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certain embodiments,the aralkyl is optionally substituted with one or more substituents Q asdescribed herein.

The term “heteroaryl” refers to a monovalent monocyclic aromatic groupor monovalent polycyclic aromatic group that contains at least onearomatic ring, wherein at least one aromatic ring contains one or moreheteroatoms independently selected from O, S, and N in the ring. Incertain embodiments, the heteroaryl is bonded to the rest of a moleculethrough the aromatic ring. Each ring of a heteroaryl group can containone or two O atoms, one or two S atoms, and/or one to four N atoms;provided that the total number of heteroatoms in each ring is four orless and each ring contains at least one carbon atom. In certainembodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to10 ring atoms. In certain embodiments, the heteroaryl is a monocyclic,bicyclic, tricyclic, or tetracyclic ring system. Examples of monocyclicheteroaryl groups include, but are not limited to, furanyl, imidazolyl,isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples ofbicyclic heteroaryl groups include, but are not limited to,benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl,benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl,benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl,indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl,isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl,pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl,thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclicheteroaryl groups include, but are not limited to, acridinyl,benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl,phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl,phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl isoptionally substituted with one or more substituents Q as describedherein.

The term “heterocyclyl” or “heterocyclic” refers to a monovalentmonocyclic non-aromatic ring system or monovalent polycyclic ring systemthat contains at least one non-aromatic ring, wherein one or more of thenon-aromatic ring atoms are heteroatoms independently selected from O,S, and N; and the remaining ring atoms are carbon atoms. In certainembodiments, the heterocyclyl has from 3 to 20, from 3 to 15, from 3 to10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certainembodiments, the heterocyclyl is bonded to the rest of a moleculethrough the non-aromatic ring. In certain embodiments, the heterocyclylis a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, whichmay be fused or bridged, and in which nitrogen or sulfur atoms may beoptionally oxidized, nitrogen atoms may be optionally quaternized, andsome rings may be partially or fully saturated, or aromatic. Theheterocyclyl may be attached to the rest of a molecule the mainstructure at any heteroatom or carbon atom, resulting in the creation ofa stable compound. Examples of such heterocyclic groups include, but arenot limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl,benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl,chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl,dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, the heterocyclic isoptionally substituted with one or more substituents Q as describedherein.

The term “halogen”, “halide,” or “halo” refers to fluorine, chlorine,bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group orsubstituent, such as an alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl, heteroaryl, and heterocyclyl group, may be substituted with oneor more substituents Q, each of which is independently selected from,e.g., (a) deuterium, cyano (—CN), halo, nitro (—NO₂), and oxo (═O); (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen ordeuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, each optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q^(a); or (iii) each pair of R^(b) and R^(e) togetherwith the N atom to which they are attached form heterocyclyl, optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q^(a). As used herein, all groups that can besubstituted are “optionally substituted,” unless otherwise specified.

In one embodiment, each Q^(a) is independently selected from the groupconsisting of (a) deuterium, cyano, halo, nitro, and oxo; and (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen ordeuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f)and R^(g) together with the N atom to which they are attached formheteroaryl or heterocyclyl.

The terms “optically active” and “enantiomerically active” refer to acollection of molecules, which has an enantiomeric excess of no lessthan about 50%, no less than about 70%, no less than about 80%, no lessthan about 90%, no less than about 91%, no less than about 92%, no lessthan about 93%, no less than about 94%, no less than about 95%, no lessthan about 96%, no less than about 97%, no less than about 98%, no lessthan about 99%, no less than about 99.5%, or no less than about 99.8%.In certain embodiments, the compound comprises about 95% or more of oneenantiomer and about 5% or less of the other enantiomer based on thetotal weight of the racemates of the compound in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of a compound about its chiralcenter(s). The (+) and (−) are used to denote the optical rotation of acompound, that is, the direction in which a plane of polarized light isrotated by the optically active compound. The (−) prefix indicates thatthe compound is levorotatory, that is, the compound rotates the plane ofpolarized light to the left or counterclockwise. The (+) prefixindicates that the compound is dextrorotatory, that is, the compoundrotates the plane of polarized light to the right or clockwise. However,the sign of optical rotation, (+) and (−), is not related to theabsolute configuration of the molecule, R and S.

The term “isotopically enriched” refers to a compound that contains anunnatural proportion of an isotope at one or more of the atoms thatconstitute such a compound. In certain embodiments, an isotopicallyenriched compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (H), deuterium (²H),tritium (³H), carbon-11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C),carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15(¹⁵N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17(¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F), fluorine-18 (¹⁸F),phosphorus-31 (³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32(³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36(³⁶S), chlorine-35 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl),bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), iodine-123 (¹²³I), iodine-125(¹²⁵I), iodine-127 (¹²⁷I), iodine-129 (¹²⁹I), and iodine-131 (¹³¹I). Incertain embodiments, an isotopically enriched compound is in a stableform, that is, non-radioactive. In certain embodiments, an isotopicallyenriched compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),carbon-12 (¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N),oxygen-16 (¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F),phosphorus-31 (³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S),sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), and iodine-127 (¹²⁷I). In certainembodiments, an isotopically enriched compound is in an unstable form,that is, radioactive. In certain embodiments, an isotopically enrichedcompound contains unnatural proportions of one or more isotopes,including, but not limited to, tritium (³H), carbon-11 (¹¹C), carbon-14(¹⁴C), nitrogen-13 (¹³N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), fluorine-18(¹⁸F), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S),chlorine-36 (³⁶Cl), iodine-123 (¹²³I), iodine-125 (¹²⁵I), iodine-129(¹²⁹I), and iodine-131 (¹³¹I). It will be understood that, in a compoundas provided herein, any hydrogen can be ²H, as example, or any carboncan be ¹³C, as example, or any nitrogen can be ¹⁵N, as example, or anyoxygen can be ¹⁸O, as example.

The term “isotopic enrichment” refers to the percentage of incorporationof a less prevalent isotope (e.g., D) of an element at a given positionin a molecule in the place of a more prevalent isotope (e.g., ¹H) of theelement. As used herein, when an atom at a particular position in amolecule is designated as a particular less prevalent isotope, it isunderstood that the abundance of that isotope at that position issubstantially greater than its natural abundance.

The term “isotopic enrichment factor” refers the ratio between theisotopic abundance in an isotopically enriched compound and the naturalabundance of a specific isotope.

The term “hydrogen” or the symbol “H” refers to the composition ofnaturally occurring hydrogen isotopes, which include protium (¹H),deuterium (²H or D), and tritium (³H), in their natural abundances.Protium is the most common hydrogen isotope having a natural abundanceof more than 99.98%. Deuterium is a less prevalent hydrogen isotopehaving a natural abundance of about 0.0156%.

The term “deuterium enrichment” refers to the percentage ofincorporation of deuterium at a given position in a molecule in theplace of hydrogen. For example, deuterium enrichment of 1% at a givenposition means that 1% of molecules in a given sample contain deuteriumat the specified position. Because the naturally occurring distributionof deuterium is about 0.0156% on average, deuterium enrichment at anyposition in a compound synthesized using non-enriched starting materialsis about 0.0156% on average. As used herein, when a particular positionin an isotopically enriched compound is designated as having deuterium,it is understood that the abundance of deuterium at that position in thecompound is substantially greater than its natural abundance (0.0156%).

The term “carbon” or the symbol “C” refers to the composition ofnaturally occurring carbon isotopes, which include carbon-12 (¹²C) andcarbon-13 (¹³C) in their natural abundances. Carbon-12 is the mostcommon carbon isotope having a natural abundance of more than 98.89%.Carbon-13 is a less prevalent hydrogen isotope having a naturalabundance of about 1.11%.

The term “carbon-13 enrichment” or “¹³C enrichment” refers to thepercentage of incorporation of carbon-13 at a given position in amolecule in the place of carbon. For example, carbon-13 enrichment of10% at a given position means that 10% of molecules in a given samplecontain carbon-13 at the specified position. Because the naturallyoccurring distribution of carbon-13 is about 1.11% on average, carbon-13enrichment at any position in a compound synthesized using non-enrichedstarting materials is about 1.11% on average. As used herein, when aparticular position in an isotopically enriched compound is designatedas having carbon-13, it is understood that the abundance of carbon-13 atthat position in the compound is substantially greater than its naturalabundance (1.11%).

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a compound provided herein, and one ormore molecules of a solvent, which present in stoichiometric ornon-stoichiometric amount. Suitable solvents include, but are notlimited to, water, methanol, ethanol, n-propanol, isopropanol, andacetic acid. In certain embodiments, the solvent is pharmaceuticallyacceptable. In one embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. Where the solvent is water, the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, andpentahydrate.

The term “naturally occurring” or “native” when used in connection withbiological materials such as nucleic acid molecules, polypeptides, andhost cells, refers to materials which are found in nature and are notmanipulated by man. Similarly, “non-naturally occurring” or “non-native”refers to a material that is not found in nature or that has beenstructurally modified or synthesized by man.

The term “CCR3” refers to CC chemokine receptor 3 or a variant thereof,which is capable of mediating a cellular response to a variety ofchemokines, including, but not limited to, eotaxin (CCL11), eotaxin-3(CCL26), MCP-3 (CCL7), MCP-4 (CCL13), and RANTES (CCL5). CCR3 variantsinclude proteins substantially homologous to a native CCR3, i.e.,proteins having one or more naturally or non-naturally occurring aminoacid deletions, insertions or substitutions (e.g., CCR3 derivatives,homologs, and fragments), as compared to the amino acid sequence of anative CCR3. The amino acid sequence of a CCR3 variant is at least about80% identical, at least about 90% identical, or at least about 95%identical to a native CCR3.

The term “CCR3 antagonist” refers to a compound that, e.g., partially ortotally blocks, decreases, prevents, inhibits, or downregulates CCR3activity. The term “CCR3 antagonist” also refers to a compound thatbinds to, delays the activation of, inactivates, or desensitizes a CCR3receptor. A CCR3 antagonist may act by interfering with the interactionof a CCR3 receptor and its chemokine ligand, including, but not limitedto, eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4 (CCL13),and/or RANTES (CCL5).

The terms “CCR3-mediated disease, disorder, or condition” and “adisease, disorder, or condition mediated by CCR3” refer to a disease,disorder, or condition characterized by abnormal or dysregulated, e.g.,greater than normal, CCR3 activity. Abnormal CCR3 functional activitymight arise as the result of CCR3 overexpression in cells, expression ofCCR3 in cells which normally do not express CCR3, or CCR3 dysregulationin cells (e.g., due to constitutively activation), leading to, e.g.,inflammatory and immune-related disorders or diseases. A CCR3-mediatedcondition, disorder or disease may be completely or partially mediatedby abnormal or dysregulated CCR3 activity. In particular, aCCR3-mediated condition, disorder or disease is one in which modulationof a CCR3 receptor results in some effect on the underlying condition ordisorder, e.g., a CCR3 antagonist results in some improvement in atleast some of patients being treated.

The phrase “an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof” has the same meaning as the phrase “an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers of the compoundreferenced therein; a pharmaceutically acceptable salt, solvate,hydrate, or prodrug of the compound referenced therein; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug of anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomers of thecompound referenced therein.”

Compounds

In one embodiment, provided herein is an arylsulfonamide of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof;wherein:

R¹, R², R³, R⁴, R⁵, and R⁸ are each independently (a) hydrogen,deuterium, halo, cyano, nitro, or guanidine; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R⁶, R⁷, and R⁹ are each independently (a) hydrogen or deuterium;

R¹⁰ is (a) hydrogen; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c);

R¹¹ is (a) deuterium, halo, cyano, nitro, oxo, or guanidine; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a) S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen,deuterium, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or each pair of R^(1b) andR^(1c) together with the N atom to which they are attached independentlyform heteroaryl or heterocyclyl;

X is O or S;

m is an integer of 0, 1, 2, or 3;

n is an integer of 1, 2, or 3; and

p is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14;

wherein the arylsulfonamide is isotopically enriched;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,heterocyclyl, and heteroaryl is optionally substituted with one or moresubstituents Q, where each Q is independently selected from (a)deuterium, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a); and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen or deuterium; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ^(a); or (iii) each pair of R^(b) and R^(e) together with the N atom towhich they are attached form heterocyclyl, optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) deuterium, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl,and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen or deuterium; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (iii) each pair of R^(f) andR^(g) together with the N atom to which they are attached formheterocyclyl.

In one embodiment, in Formula I,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, deuterium, halo,or C₁₋₆ alkyl optionally substituted with one or more substituents Q;

R⁶, R⁷, and R⁹ are each independently hydrogen or deuterium;

R⁸ is cyano or nitro;

R¹⁰ is (a) hydrogen or deuterium; (b) C₁₋₆ alkyl or C₃₋₇ cycloalkyl,each optionally substituted with one or more substituents Q; or (c)—C(O)R^(1a), —C(O)NR^(1b)R^(1c), or —S(O)₂R^(1a); wherein R^(1a) andR^(1c) are each independently C₁₋₆ alkyl; C₃₋₇ cycloalkyl, optionallysubstituted with one or two C₁₋₆ alkyl; or C₆₋₁₄ aryl, optionallysubstituted with one or more halo or C₁₋₆ alkyl, where the alkyl isfurther optionally substituted with one, two, or three halo; and R^(1b)is hydrogen or deuterium;

each R¹¹ is independently deuterium or C₁₋₆ alkyl optionally substitutedwith one or more substituents Q;

X is O or S;

m is an integer of 0, 1, or 2;

n is an integer of 1 or 2; and

p is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In another embodiment, in Formula I,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, deuterium, halo,or C₁₋₆ alkyl optionally substituted with one or more substituents Q;

R⁶, R⁷, and R⁹ are each independently hydrogen or deuterium;

R⁸ is cyano or nitro;

R¹⁰ is hydrogen or deuterium;

each R¹¹ is independently deuterium or C₁₋₆ alkyl optionally substitutedwith one or more substituents Q;

X is O or S;

m is an integer of 0, 1, or 2;

n is an integer of 1 or 2; and

p is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In yet another embodiment, in Formula I,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, deuterium,chloro, or methyl;

R⁶, R⁷, and R⁹ are each independently hydrogen or deuterium;

R⁸ is cyano or nitro;

R¹⁰ is hydrogen, deuterium, methyl, —CD₃, cyclopentyl, —C(O)R^(1a),—C(O)NR^(1b)R^(1c), or —S(O)₂R^(1a); wherein R^(1a) and R^(1c) are eachindependently methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl(e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g., n-pentyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, or 2,2-dimethylpropyl), cyclobutyl, cyclopentyl,cyclohexyl, dimethylbicyclo[2.2.1]heptyl (e.g.,7,7-dimethylbicyclo[2.2.1]-heptyl), phenyl, fluorophenyl (e.g.,2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl), chlorophenyl (e.g.,2-chlorophenyl, 3-chlorophenyl, or 4-chlorophenyl), methylphenyl (e.g.,2-methylphenyl, 3-methylphenyl, or 4-methylphenyl),trifluoromethylphenyl (e.g., 2-trifluoromethylphenyl,3-trifluoromethylphenyl, or 4-trifluoromethylphenyl), or ethylphenyl(e.g., 2-ethylphenyl, 3-ethylphenyl, or 4-ethylphenyl); and R^(1b) ishydrogen or deuterium;

R¹¹ is deuterium;

X is O or S;

m is an integer of 0, 1, or 2;

n is an integer of 1 or 2; and

p is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In yet another embodiment, in Formula I,

R¹, R³, R⁵, R⁶, R⁷, and R⁹ are each independently hydrogen or deuterium;

R² and R⁴ are each independently chloro or methyl;

R⁸ is cyano;

R¹⁰ is hydrogen, deuterium, methyl, —CD₃, cyclopentyl, —C(O)R^(1a),—C(O)NR^(1b)R^(1c), or —S(O)₂R^(1a); wherein R^(1a) and R^(1c) are eachindependently methyl, ethyl, isopropyl, isobutyl, t-butyl,1,1-dimethylpropyl, 2,2-dimethylpropyl, cyclobutyl, cyclopentyl,cyclohexyl, (1S,2S,4R)-7,7-dimethylbicyclo[2.2.1]-heptyl, phenyl,2-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,4-trifluoromethylphenyl, or 4-ethylphenyl; and R^(b) is hydrogen ordeuterium;

R¹¹ is deuterium;

X is O or S;

m is an integer of 1;

n is an integer of 1; and

p is an integer of 1, 2, 3, 4, 5, or 6.

In yet another embodiment, in Formula I,

R¹, R³, R⁵, R⁶, R⁷, and R⁹ are each independently hydrogen or deuterium;

R² and R⁴ are each independently chloro or methyl;

R⁸ is cyano;

R¹⁰ is hydrogen or deuterium;

R¹¹ is deuterium;

X is O or S;

m is an integer of 1;

n is an integer of 1; and

p is an integer of 1, 2, 3, 4, 5, or 6.

In still another embodiment, in Formula I,

R¹, R³, R⁵, R⁶, R⁷, and R⁹ are each independently hydrogen or deuterium;

R² and R⁴ are chloro;

R⁸ is cyano;

R¹⁰ is hydrogen or deuterium;

R¹¹ is deuterium;

X is O or S;

m is an integer of 1;

n is an integer of 1; and

p is an integer of 1, 2, 3, 4, 5, or 6.

In another embodiment, provided herein is an arylsulfonamide of FormulaII:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof;wherein:

R^(11a), R^(11b), R^(11c), R^(11d), R^(11e), and R^(11f) are eachindependently hydrogen or deuterium; and

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and X are each as definedherein;

wherein the arylsulfonamide is isotopically enriched.

In one embodiment, in Formula II,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, deuterium, halo,or C₁₋₆ alkyl optionally substituted with one or more substituents Q;

R⁶, R⁷, R⁹, R^(11a), R^(11b), R^(11c), R^(11d), R^(11e), and R^(11f) areeach independently hydrogen or deuterium;

R⁸ is cyano or nitro;

R¹⁰ is (a) hydrogen or deuterium; (b) C₁₋₆ alkyl or C₃₋₇ cycloalkyl,each of optionally substituted with one or more substituents Q; or (c)—C(O)R^(1a), —C(O)NR^(1b)R^(1c), or —S(O)₂R^(1a); wherein R^(1a) andR^(1c) are each independently C₁₋₆ alkyl; C₃₋₇ cycloalkyl, optionallysubstituted with one or two C₁₋₆ alkyl; or C₆₋₁₄ aryl, optionallysubstituted with one or more halo or C₁₋₆ alkyl, where the alkyl isfurther optionally substituted with one, two, or three halo; and R^(1b)is hydrogen or deuterium; and

X is O or S.

In another embodiment, in Formula II,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, deuterium, halo,or C₁₋₆ alkyl optionally substituted with one or more substituents Q;

R⁶, R⁷, R⁹, R¹⁰, R^(11a), R^(11b), R^(11c), R^(11d), R^(11e), andR^(11f) are each independently hydrogen or deuterium;

R⁸ is cyano or nitro; and

X is O or S.

In yet another embodiment, in Formula II,

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, deuterium,chloro, or methyl;

R⁶, R⁷, R⁹, R^(11a), R^(11b), R^(11c), R^(11d), R^(11e), and R^(11f) areeach independently hydrogen or deuterium;

R⁸ is cyano or nitro;

R¹⁰ is hydrogen, deuterium, methyl, —CD₃, cyclopentyl, —C(O)R^(1a),—C(O)NR^(1b)R^(1c), or —S(O)₂R^(1a); wherein R^(1a) and R^(1c) are eachindependently methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl(e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g., n-pentyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, or 2,2-dimethylpropyl), cyclobutyl, cyclopentyl,cyclohexyl, dimethylbicyclo[2.2.1]heptyl (e.g.,7,7-dimethylbicyclo[2.2.1]-heptyl), phenyl, fluorophenyl (e.g.,2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl), chlorophenyl (e.g.,2-chlorophenyl, 3-chlorophenyl, or 4-chlorophenyl), methylphenyl (e.g.,2-methylphenyl, 3-methylphenyl, or 4-methylphenyl),trifluoromethylphenyl (e.g., 2-trifluoromethylphenyl,3-trifluoromethylphenyl, or 4-trifluoromethylphenyl), or ethylphenyl(e.g., 2-ethylphenyl, 3-ethylphenyl, or 4-ethylphenyl); and R^(1b) ishydrogen or deuterium; and

X is O or S.

In yet another embodiment, in Formula II,

R¹, R³, R⁵, R⁶, R⁷, R⁹, R^(11a), R^(11b), R^(11c), R^(11d), R^(11e), andR^(11f) are each independently hydrogen or deuterium;

R² and R⁴ are each independently chloro or methyl;

R⁸ is cyano;

R¹⁰ is hydrogen, deuterium, methyl, —CD₃, cyclopentyl, —C(O)R^(a),—C(O)NR^(1b)R^(1c), or —S(O)₂R^(1a); wherein R^(1a) and R^(1c) are eachindependently methyl, ethyl, isopropyl, isobutyl, t-butyl,1,1-dimethylpropyl, 2,2-dimethylpropyl, cyclobutyl, cyclopentyl,cyclohexyl, (1S,2S,4R)-7,7-dimethylbicyclo[2.2.1]-heptyl, phenyl,2-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,4-trifluoromethylphenyl, or 4-ethylphenyl; and R^(1b) is hydrogen ordeuterium; and

X is O or S.

In yet another embodiment, in Formula II,

R¹, R³, R⁵, R⁶, R⁷, R⁹, R¹⁰, R^(11a), R^(11b), R^(11c), R^(11d),R^(11e), and R^(11f) are each independently hydrogen or deuterium;

R² and R⁴ are each independently chloro or methyl;

R⁸ is cyano; and

X is O or S.

In still another embodiment, in Formula II,

R¹, R³, R⁵, R⁶, R⁷, R⁹, R¹⁰, R^(11a), R^(11b), R^(11c), R^(11d),R^(11e), and R^(11f) are each independently hydrogen or deuterium;

R² and R⁴ are chloro;

R⁸ is cyano; and

X is O or S.

In yet another embodiment, provided herein is an arylsulfonamide ofFormula III:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; wherein R¹, R³, R⁵, R⁶, R⁷, R⁹, R¹⁰, R^(11a), R^(11b),R^(11c), R^(11d), R^(11e), R^(11f), and X are each as defined herein;and wherein the arylsulfonamide is isotopically enriched.

In still another embodiment, provided herein is an arylsulfonamide ofFormula IV:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; wherein R¹, R³, R⁵, R⁶, R⁷, R⁹, R¹⁰, R^(11a), R^(11b),R^(11c), R^(11d), R^(11e), and R^(11f) are each as defined herein; andwherein the arylsulfonamide is isotopically enriched.

The groups, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(1a),R^(1b), R^(1c), R^(1d), R^(11a), R^(11a), R^(11b), R^(11c), R^(11d),R^(11e), R^(11f), X, m, n, and p in formulae described herein, includingFormulae I to IV, are further defined in the embodiments describedherein. All combinations of the embodiments provided herein for suchgroups are within the scope of this disclosure.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ isdeuterium. In certain embodiments, R¹ is halo. In certain embodiments,R¹ is fluoro, chloro, bromo, or iodo. In certain embodiments, R¹ isfluoro. In certain embodiments, R¹ is chloro. In certain embodiments, R¹is cyano. In certain embodiments, R¹ is —¹³CN. In certain embodiments,R¹ is nitro. In certain embodiments, R¹ is guanidine. In certainembodiments, R¹ is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R¹ is C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo. In certain embodiments, R¹ ismethyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g.,n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g., n-pentyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, or 2,2-dimethylpropyl). In certain embodiments, R¹is methyl, —CH₂D, —CHD₂, or —CD₃. In certain embodiments, R¹ is C₂₋₆alkenyl, optionally substituted with one or more substituents Q. Incertain embodiments, R¹ is C₂₋₆ alkynyl, optionally substituted with oneor more substituents Q. In certain embodiments, R¹ is C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R¹ is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R¹ is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R¹is heteroaryl, optionally substituted with one or more substituents Q.In certain embodiments, R¹ is heterocyclyl, optionally substituted withone or more substituents Q.

In certain embodiments, R¹ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R¹ is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R¹ is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R¹ is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R¹ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R¹ is —OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R¹ is —OR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R¹ is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R¹ is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R¹ is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R¹ is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R¹ is —OS(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R¹ is —OS(O)₂R^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R¹ is —OS(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R¹ is —OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹ is —NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R¹ is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R¹ is—NR^(a)C(O)OR^(1d), wherein R^(a) and R^(d) are each as defined herein.In certain embodiments, R¹ is —NR^(1a)C(O)NR^(1b)R^(1c), wherein R^(1a),R^(1b), and R^(1c) are each as defined herein. In certain embodiments,R¹ is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c),and R^(1d) are each as defined herein. In certain embodiments, R is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R is —NR^(1a)S(O)₂R^(1d), wherein R^(1a)and R^(1d) are each as defined herein. In certain embodiments, R is—NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R¹ is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R¹ is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R¹ is —SR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R¹ is —SR^(1a), wherein R^(1a)is C₁₋₆ alkyl, optionally substituted with one, two, or three halo. Incertain embodiments, R¹ is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R¹ is —S(O)₂R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R¹ is —S(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R¹ is —S(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein.

In certain embodiments, R² is hydrogen. In certain embodiments, R² isdeuterium. In certain embodiments, R² is halo. In certain embodiments,R² is fluoro, chloro, bromo, or iodo. In certain embodiments, R² isfluoro. In certain embodiments, R² is chloro. In certain embodiments, R²is cyano. In certain embodiments, R² is —¹³CN. In certain embodiments,R² is nitro. In certain embodiments, R² is guanidine. In certainembodiments, R² is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R² is C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo. In certain embodiments, R² ismethyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g.,n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g., n-pentyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, or 2,2-dimethylpropyl). In certain embodiments, R²is methyl, —CH₂D, —CHD₂, or —CD₃. In certain embodiments, R² is C₂₋₆alkenyl, optionally substituted with one or more substituents Q. Incertain embodiments, R² is C₂₋₆ alkynyl, optionally substituted with oneor more substituents Q. In certain embodiments, R² is C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R² is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R² is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R²is heteroaryl, optionally substituted with one or more substituents Q.In certain embodiments, R² is heterocyclyl, optionally substituted withone or more substituents Q.

In certain embodiments, R² is —C(O)R^(a), wherein R^(1a) is as definedherein. In certain embodiments, R² is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R² is —C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R² is —C(NR^(1a))NR^(1b)R^(c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R² is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R² is —OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R² is —OR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R² is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R² is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R² is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R² is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R² is —OS(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R² is —OS(O)₂R^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R² is —OS(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R² is —OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R² is —NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R² is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R² is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R² is —NR^(1a)C(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R² is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein. In certainembodiments, R² is —NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R² is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R² is —NR^(1a)S(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R² is —NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R² is—SR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R² is —SR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R² is —SR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R² is —S(O)R^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R² is —S(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R² is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R² is —S(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ isdeuterium. In certain embodiments, R³ is halo. In certain embodiments,R³ is fluoro, chloro, bromo, or iodo. In certain embodiments, R³ isfluoro. In certain embodiments, R³ is chloro. In certain embodiments, R³is cyano. In certain embodiments, R³ is —¹³CN. In certain embodiments,R³ is nitro. In certain embodiments, R³ is guanidine. In certainembodiments, R³ is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R³ is C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo. In certain embodiments, R³ ismethyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g.,n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g., n-pentyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, or 2,2-dimethylpropyl). In certain embodiments, R³is methyl, —CH₂D, —CHD₂, or —CD₃. In certain embodiments, R³ is C₂₋₆alkenyl, optionally substituted with one or more substituents Q. Incertain embodiments, R³ is C₂₋₆ alkynyl, optionally substituted with oneor more substituents Q. In certain embodiments, R³ is C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R³ is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R³ is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R³is heteroaryl, optionally substituted with one or more substituents Q.In certain embodiments, R³ is heterocyclyl, optionally substituted withone or more substituents Q.

In certain embodiments, R³ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R³ is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R³ is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R³ is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R³ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R³ is —OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R³ is —OR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R³ is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R³ is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R³ is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R³ is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R³ is —OS(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R³ is —OS(O)₂R^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R³ is —OS(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R³ is —OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R³ is —NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R³ is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R³ is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R³ is —NR^(1a)C(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R³ is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein. In certainembodiments, R³ is —NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R³ is—NR^(1a)S(O)₂R^(1d), wherein R^(a) and R^(d) are each as defined herein.In certain embodiments, R³ is —NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a),R^(1b), and R^(1c) are each as defined herein. In certain embodiments,R³ is —NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) areeach as defined herein. In certain embodiments, R³ is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R³ is —SR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R³ is —SR^(1a), wherein R^(1a)is C₁₋₆ alkyl, optionally substituted with one, two, or three halo. Incertain embodiments, R³ is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R³ is —S(O)₂R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R³ is —S(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R³ is —S(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein.

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ isdeuterium. In certain embodiments, R⁴ is halo. In certain embodiments,R⁴ is fluoro, chloro, bromo, or iodo. In certain embodiments, R⁴ isfluoro. In certain embodiments, R⁴ is chloro. In certain embodiments, R⁴is cyano. In certain embodiments, R⁴ is —¹³CN. In certain embodiments,R⁴ is nitro. In certain embodiments, R⁴ is guanidine. In certainembodiments, R⁴ is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁴ is C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo. In certain embodiments, R⁴ ismethyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g.,n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g., n-pentyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, or 2,2-dimethylpropyl). In certain embodiments, R⁴is methyl, —CH₂D, —CHD₂, or —CD₃. In certain embodiments, R⁴ is C₂₋₆alkenyl, optionally substituted with one or more substituents Q. Incertain embodiments, R⁴ is C₂₋₆ alkynyl, optionally substituted with oneor more substituents Q. In certain embodiments, R⁴ is C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁴ is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁴ is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁴is heteroaryl, optionally substituted with one or more substituents Q.In certain embodiments, R⁴ is heterocyclyl, optionally substituted withone or more substituents Q.

In certain embodiments, R⁴ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁴ is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R⁴ is —C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁴ is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R⁴ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R⁴ is —OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R⁴ is —OR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R⁴ is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R⁴ is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R⁴ is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R⁴ is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R⁴ is —OS(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁴ is —OS(O)₂R^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R⁴ is —OS(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁴ is —OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R⁴ is —NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁴ is —NR^(1a)C(O)R^(1d), wherein R and R^(1d) are each asdefined herein. In certain embodiments, R⁴ is —NR^(1a)C(O)OR^(1d),wherein R^(1a) and R^(1d) are each as defined herein. In certainembodiments, R⁴ is —NR^(1a)C(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R⁴ is—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R⁴ is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R⁴ is —NR^(1a)S(O)₂R^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments, R⁴is —NR^(a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R⁴ is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R⁴ is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R⁴ is —SR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁴ is —SR^(1a), wherein R^(1a)is C₁₋₆ alkyl, optionally substituted with one, two, or three halo. Incertain embodiments, R⁴ is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁴ is —S(O)₂R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R⁴ is —S(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁴ is —S(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein.

In certain embodiments, R⁵ is hydrogen. In certain embodiments, R⁵ isdeuterium. In certain embodiments, R⁵ is halo. In certain embodiments,R⁵ is fluoro, chloro, bromo, or iodo. In certain embodiments, R⁵ isfluoro. In certain embodiments, R⁵ is chloro. In certain embodiments, R⁵is cyano. In certain embodiments, R⁵ is —¹³CN. In certain embodiments,R⁵ is nitro. In certain embodiments, R⁵ is guanidine. In certainembodiments, R⁵ is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁵ is C₁₋₆ alkyl, optionallysubstituted with one, two, or three halo. In certain embodiments, R⁵ ismethyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g.,n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g., n-pentyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, or 2,2-dimethylpropyl). In certain embodiments, R⁵is methyl, —CH₂D, —CHD₂, or —CD₃. In certain embodiments, R⁵ is C₂₋₆alkenyl, optionally substituted with one or more substituents Q. Incertain embodiments, R⁵ is C₂₋₆ alkynyl, optionally substituted with oneor more substituents Q. In certain embodiments, R⁵ is C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁵ is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁵ is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁵is heteroaryl, optionally substituted with one or more substituents Q.In certain embodiments, R⁵ is heterocyclyl, optionally substituted withone or more substituents Q.

In certain embodiments, R⁵ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁵ is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R⁵ is —C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁵ is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R⁵ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R⁵ is —OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R⁵ is —OR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R⁵ is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R⁵ is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R⁵ is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R⁵ is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R⁵ is —OS(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁵ is —OS(O)₂R^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R⁵ is —OS(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁵ is —OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R⁵ is —NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁵ is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R⁵ is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R⁵ is —NR^(1a)C(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R⁵ is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein. In certainembodiments, R⁵ is —NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R⁵ is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R is —NR^(1a)S(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R⁵ is —NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R⁵ is—SR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R⁵ is —SR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R⁵ is —SR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R⁵ is —S(O)R^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R⁵ is —S(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R⁵ is —S(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, two of R¹, R², R³, R⁴, and R⁵ are halo or C₁₋₆alkyl optionally substituted with one or more substituents Q. In certainembodiments, two of R¹, R², R³, R⁴, and R⁵ are halo or C₁₋₆ alkyloptionally substituted with one or more substituents Q, and theremaining three are hydrogen or deuterium. In certain embodiments, twoof R¹, R², R³, R⁴, and R⁵ are halo or C₁₋₆ alkyl optionally substitutedwith one or more substituents Q, and the remaining three are deuterium.In certain embodiments, two of R¹, R², R³, R⁴, and R⁵ are chloro,methyl, —CH₂D, —CHD₂, or —CD₃. In certain embodiments, two of R¹, R²,R³, R⁴, and R⁵ are chloro, methyl, —CH₂D, —CHD₂, or —CD₃, and theremaining three are hydrogen or deuterium. In certain embodiments, twoof R¹, R², R³, R⁴, and R⁵ are chloro, methyl, —CH₂D, —CHD₂, or —CD₃, andthe remaining three are deuterium.

In certain embodiments, R¹, R³, and R⁵ are hydrogen or deuterium, and R²and R⁴ are halo or C₁₋₆ alkyl optionally substituted with one or moresubstituents Q. In certain embodiments, R¹, R³, and R⁵ are deuterium,and R² and R⁴ are halo or C₁₋₆ alkyl optionally substituted with one ormore substituents Q. In certain embodiments, R¹, R³, and R⁵ are hydrogenor deuterium, and R² and R⁴ are chloro, methyl, —CH₂D, —CHD₂, or —CD₃.In certain embodiments, R¹, R³, and R⁵ are deuterium, and R² and R⁴ arechloro, methyl, —CH₂D, —CHD₂, or —CD₃. In certain embodiments, R¹, R³,and R⁵ are hydrogen or deuterium, and R² and R⁴ are chloro. In certainembodiments, R¹, R³, and R⁵ are deuterium, and R² and R⁴ are chloro. Incertain embodiments, R¹, R³, and R⁵ are hydrogen or deuterium, and R²and R⁴ are methyl, —CH₂D, —CHD₂, or —CD₃. In certain embodiments, R¹,R³, and R⁵ are deuterium, and R² and R⁴ are methyl, —CH₂D, —CHD₂, or—CD₃.

In certain embodiments, R², R³, and R⁵ are hydrogen or deuterium, and R¹and R⁴ are halo or C₁₋₆ alkyl optionally substituted with one or moresubstituents Q. In certain embodiments, R², R³, and R⁵ are deuterium,and R¹ and R⁴ are halo or C₁₋₆ alkyl optionally substituted with one ormore substituents Q. In certain embodiments, R², R³, and R⁵ are hydrogenor deuterium, and R¹ and R⁴ are chloro, methyl, —CH₂D, —CHD₂, or —CD₃.In certain embodiments, R², R³, and R⁵ are deuterium, and R¹ and R⁴ arechloro, methyl, —CH₂D, —CHD₂, or —CD₃. In certain embodiments, R², R³,and R⁵ are hydrogen or deuterium, and R¹ and R⁴ are chloro. In certainembodiments, R², R³, and R⁵ are deuterium, and R¹ and R⁴ are chloro. Incertain embodiments, R², R³, and R⁵ are hydrogen or deuterium, and R¹and R⁴ are methyl, —CH₂D, —CHD₂, or —CD₃. In certain embodiments, R²,R³, and R⁵ are deuterium, and R¹ and R⁴ are methyl, —CH₂D, —CHD₂, or—CD₃.

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ isdeuterium.

In certain embodiments, R⁷ is hydrogen. In certain embodiments, R⁷ isdeuterium.

In certain embodiments, R⁸ is hydrogen. In certain embodiments, R⁸ isdeuterium. In certain embodiments, R⁸ is halo. In certain embodiments,R⁸ is fluoro, chloro, bromo, or iodo. In certain embodiments, R⁸ isfluoro. In certain embodiments, R⁸ is chloro. In certain embodiments, R⁸is cyano. In certain embodiments, R⁸ is —¹²CN. In certain embodiments,R⁸ is —¹³CN. In certain embodiments, R⁸ is —¹⁴CN. In certainembodiments, R is nitro. In certain embodiments, R⁸ is guanidine. Incertain embodiments, R⁸ is C₁₋₆ alkyl, optionally substituted with oneor more substituents Q. In certain embodiments, R⁸ is C₁₋₆ alkyl,optionally substituted with one, two, or three halo. In certainembodiments, R⁸ is methyl, ethyl, propyl (e.g., n-propyl or isopropyl),butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl (e.g.,n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, or 2,2-dimethylpropyl). Incertain embodiments, R⁸ is methyl, —CH₂D, —CHD₂, or —CD₃. In certainembodiments, R⁸ is C₂₋₆ alkenyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁸ is C₂₋₆ alkynyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁸is C₃₋₇ cycloalkyl, optionally substituted with one or more substituentsQ. In certain embodiments, R⁸ is C₆₋₁₄ aryl, optionally substituted withone or more substituents Q. In certain embodiments, R⁸ is C₇₋₁₅ aralkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁸ is heteroaryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁸ is heterocyclyl, optionallysubstituted with one or more substituents Q.

In certain embodiments, R⁸ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁸ is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R⁸ is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁸ is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R⁸ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R⁸ is —OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R⁸ is —OR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R⁸ is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R⁸ is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R⁸ is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R⁸ is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R⁸ is —OS(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁸ is —OS(O)₂R^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R⁸ is —OS(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁸ is —OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R⁸ is —NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁸ is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R⁸ is—NR^(a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R⁸ is —NR^(1a)C(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R⁸ is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein. In certainembodiments, R⁸ is —NR^(1a)S(O)R^(d), wherein R^(1a) and R^(1d) are eachas defined herein. In certain embodiments, R⁸ is —NR^(1a)S(O)₂R^(1d),wherein R^(1a) and R^(1d) are each as defined herein. In certainembodiments, R⁸ is —NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R⁸ is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R⁸ is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R⁸ is —SR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁸ is —SR^(1a), wherein R^(1a)is C₁₋₆ alkyl, optionally substituted with one, two, or three halo. Incertain embodiments, R⁸ is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁸ is —S(O)₂R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R⁸ is —S(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁸ is —S(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein.

In certain embodiments, R⁹ is hydrogen. In certain embodiments, R⁹ isdeuterium.

In certain embodiments, at least one of R⁶, R⁷, and R⁹ is deuterium. Incertain embodiments, at least two of R⁶, R⁷, and R⁹ are deuterium. Incertain embodiments, R⁶, R⁷, and R⁹ are deuterium.

In certain embodiments, R¹⁰ is hydrogen. In certain embodiments, R¹⁰ isC₁₋₆ alkyl, optionally substituted with one or more substituents Q. Incertain embodiments, R¹⁰ is methyl, —CH₂D, —CHD₂, or —CD₃. In certainembodiments, R¹⁰ is C₂₋₆ alkenyl, optionally substituted with one ormore substituents Q. In certain embodiments, R¹⁰ is C₂₋₆ alkynyl,optionally substituted with one or more substituents Q. In certainembodiments, R¹⁰ is C₃₋₇ cycloalkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R¹⁰ is cyclopentyl. Incertain embodiments, R¹⁰ is C₆₋₁₄ aryl, optionally substituted with oneor more substituents Q. In certain embodiments, R¹⁰ is C₇₋₁₅ aralkyl,optionally substituted with one or more substituents Q. In certainembodiments, R¹⁰ is heteroaryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R¹⁰ is heterocyclyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R¹⁰is —C(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹⁰ is not —C(O)H. In certain embodiments, R¹⁰ is—C(O)OR^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹⁰ is —C(O)OR^(1a), wherein R^(1a) is as defined herein,but R^(1a) is not -t-butyl, 9-fluorenylmethyl, or benzyl. In certainembodiments, R¹⁰ is not —C(O)O—C₁₋₆ alkyl. In certain embodiments, R¹⁰is —C(O)O—C₁₋₆ alkyl, but not —C(O)O-t-butyl. In certain embodiments,R¹⁰ is —C(O)O-ethyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R¹⁰ is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R¹⁰ is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R¹⁰ is—S(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹⁰ is —S(O)₂R^(1a), wherein R^(1a) is as defined herein.In certain embodiments, R¹⁰ is —S(O)NR^(1b)R^(1c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R¹⁰ is—S(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein.

In certain embodiments, R¹¹ is hydrogen. In certain embodiments, R¹¹ isdeuterium. In certain embodiments, R¹¹ is halo. In certain embodiments,R¹¹ is fluoro, chloro, bromo, or iodo. In certain embodiments, R¹¹ isfluoro. In certain embodiments, R¹¹ is chloro. In certain embodiments,R¹¹ is cyano. In certain embodiments, R¹¹ is —¹³CN. In certainembodiments, R¹¹ is nitro. In certain embodiments, R¹¹ is oxo. Incertain embodiments, R¹¹ is guanidine. In certain embodiments, R¹¹ isC₁₋₆ alkyl, optionally substituted with one or more substituents Q. Incertain embodiments, R¹¹ is C₁₋₆ alkyl, optionally substituted with one,two, or three halo. In certain embodiments, R¹¹ is methyl, ethyl, propyl(e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl,or t-butyl), pentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R¹¹ is methyl, —CH₂D,—CHD₂, or —CD₃. In certain embodiments, R¹¹ is C₂₋₆ alkenyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R¹¹is C₂₋₆ alkynyl, optionally substituted with one or more substituents Q.In certain embodiments, R¹¹ is C₃₋₇ cycloalkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R¹¹ is C₆₋₁₄aryl, optionally substituted with one or more substituents Q. In certainembodiments, R¹¹ is C₇₋₁₅ aralkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R¹¹ is heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R¹¹ is heterocyclyl, optionally substituted with one ormore substituents Q.

In certain embodiments, R¹¹ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R¹¹ is —C(O)OR^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R¹¹ is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R¹¹ is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R¹¹ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R¹¹ is —OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R¹¹ is—OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one,two, or three halo. In certain embodiments, R¹¹ is —OC(O)R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R¹¹ is—OC(O)OR^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹¹ is —OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹¹ is—OC(═NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R¹¹ is —OS(O)R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R¹¹ is—OS(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹¹ is —OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹¹ is—OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R¹¹ is —NR^(1b)R^(1c), wherein R^(1b)and R^(1c) are each as defined herein. In certain embodiments, R¹¹ is—NR^(1a)C(O)R^(1d), wherein R and R^(1d) are each as defined herein. Incertain embodiments, R¹¹ is —NR^(1a)C(O)OR^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R¹¹ is—NR^(1a)C(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R¹¹ is—NR^(1a)C(═NR^(d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R¹¹ is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R¹¹ is —NR^(1a)S(O)₂R^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments,R¹¹ is —NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) areeach as defined herein. In certain embodiments, R¹¹ is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R¹¹ is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R¹¹ is —SR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R¹¹ is —SR^(1a), wherein R^(1a)is C₁₋₆ alkyl, optionally substituted with one, two, or three halo. Incertain embodiments, R¹¹ is —S(O)R^(a), wherein R^(1a) is as definedherein. In certain embodiments, R¹¹ is —S(O)₂R^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R¹¹ is —S(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R¹¹ is —S(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein.

In certain embodiments, X is O. In certain embodiments, X is ¹⁵O. Incertain embodiments, X is ¹⁶O. In certain embodiments, X is ¹⁷O. Incertain embodiments, X is ¹⁸O. In certain embodiments, X is ¹⁸O. Incertain embodiments, X is S. In certain embodiments, X is ³²S. Incertain embodiments, X is ³³S. In certain embodiments, X is ³⁴S. Incertain embodiments, X is ³⁵S. In certain embodiments, X is ³⁶S.

In certain embodiments, m is 0. In certain embodiments, m is 1. Incertain embodiments, m is 2. In certain embodiments, m is 3.

In certain embodiments, n is 1. In certain embodiments, n is 2. Incertain embodiments, n is 3.

In certain embodiments, m is 1 and n is 1. In certain embodiments, m is1 and n is 2.

In certain embodiments, p is 1. In certain embodiments, p is 2. Incertain embodiments, p is 3. In certain embodiments, p is 4. In certainembodiments, p is 5. In certain embodiments, p is 6. In certainembodiments, p is 7. In certain embodiments, p is 8. In certainembodiments, p is 9. In certain embodiments, p is 10. In certainembodiments, p is 11. In certain embodiments, p is 12. In certainembodiments, p is 13. In certain embodiments, p is 14.

In certain embodiments, R^(1a) is hydrogen. In certain embodiments,R^(1a) is deuterium. In certain embodiments, R^(1a) is C₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1a) is methyl, ethyl, propyl (e.g., n-propyl orisopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), orpentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R^(1a) is methyl, ethyl,isopropyl, isobutyl, t-butyl, 1,1-dimethylpropyl, or 2,2-dimethylpropyl.In certain embodiments, R^(1a) is C₂₋₆ alkenyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(1a) is C₂₋₆alkynyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(1a) is C₃₋₇ cycloalkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(1a) is C₃₋₇cycloalkyl, optionally substituted with one or two C₁₋₆ alkyl. Incertain embodiments, R^(1a) is C₃₋₇ cycloalkyl, optionally substitutedwith two methyl groups. In certain embodiments, R^(1a) is cyclobutyl,cyclopentyl, cyclohexyl, or dimethylbicyclo-[2.2.1]heptyl (e.g.,7,7-dimethylbicyclo[2.2.1]-heptyl). In certain embodiments, R^(1a) iscyclobutyl, cyclopentyl, cyclohexyl, or(1S,2S,4R)-7,7-dimethylbicyclo[2.2.1]-heptyl. In certain embodiments,R^(1a) is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(1a) is C₆₋₁₄ aryl, optionallysubstituted with one or more halo or C₁₋₆ alkyl, wherein the alkyl isoptionally substituted with one, two, or three halo. In certainembodiments, R^(1a) is C₆₋₁₄ aryl, optionally substituted with fluoro,chloro, methyl, trifluoromethyl, or ethyl. In certain embodiments,R^(1a) is phenyl, fluorophenyl (e.g., 2-fluorophenyl, 3-fluorophenyl, or4-fluorophenyl), chlorophenyl (e.g., 2-chlorophenyl, 3-chlorophenyl, or4-chlorophenyl), methylphenyl (e.g., 2-methylphenyl, 3-methylphenyl, or4-methylphenyl), trifluoromethylphenyl (e.g., 2-trifluoromethylphenyl,3-trifluoromethylphenyl, or 4-trifluoromethylphenyl), or ethylphenyl(e.g., 2-ethylphenyl, 3-ethylphenyl, or 4-ethylphenyl). In certainembodiments, R^(1a) is phenyl, 3-fluorophenyl, 3-methylphenyl,4-chlorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, or4-ethylphenyl. In certain embodiments, R^(1a) is heteroaryl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(1a) is heterocyclyl, optionally substituted with one or moresubstituents Q.

In certain embodiments, R^(1b) is hydrogen. In certain embodiments,R^(1b) is deuterium. In certain embodiments, R^(1b) is C₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1b) is C₂₋₆ alkenyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1b) is C₂₋₆ alkynyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1b) is C₃₋₇ cycloalkyl, optionally substituted with oneor more substituents Q. In certain embodiments, R^(1b) is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1b) is heteroaryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1b) is heterocyclyl,optionally substituted with one or more substituents Q.

In certain embodiments, R^(1c) is hydrogen. In certain embodiments,R^(1c) is deuterium. In certain embodiments, R^(1c) is C₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1c) is methyl, ethyl, propyl (e.g., n-propyl orisopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), orpentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R^(1c) is methyl, ethyl,isopropyl, isobutyl, t-butyl, 1,1-dimethylpropyl, or 2,2-dimethylpropyl.In certain embodiments, R^(1c) is C₂₋₆ alkenyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(1c) is C₂₋₆alkynyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(1c) is C₃₋₇ cycloalkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(1c) is C₃₋₇cycloalkyl, optionally substituted with one or two C₁₋₆ alkyl. Incertain embodiments, R^(1c) is C₃₋₇ cycloalkyl, optionally substitutedwith two methyl groups. In certain embodiments, R^(1c) is cyclobutyl,cyclopentyl, cyclohexyl, or dimethylbicyclo-[2.2.1]heptyl (e.g.,7,7-dimethylbicyclo[2.2.1]-heptyl). In certain embodiments, R^(1c) iscyclobutyl, cyclopentyl, cyclohexyl, or(1S,2S,4R)-7,7-dimethylbicyclo[2.2.1]-heptyl. In certain embodiments,R^(1c) is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(1c) is C₆₋₁₄ aryl, optionallysubstituted with one or more halo or C₁₋₆ alkyl, wherein the alkyl isoptionally substituted with one, two, or three halo. In certainembodiments, R^(1c) is C₆₋₁₄ aryl, optionally substituted with fluoro,chloro, methyl, trifluoromethyl, or ethyl. In certain embodiments,R^(1c) is phenyl, fluorophenyl (e.g., 2-fluorophenyl, 3-fluorophenyl, or4-fluorophenyl), chlorophenyl (e.g., 2-chlorophenyl, 3-chlorophenyl, or4-chlorophenyl), methylphenyl (e.g., 2-methylphenyl, 3-methylphenyl, or4-methylphenyl), trifluoromethylphenyl (e.g., 2-trifluoromethylphenyl,3-trifluoromethylphenyl, or 4-trifluoromethylphenyl), or ethylphenyl(e.g., 2-ethylphenyl, 3-ethylphenyl, or 4-ethylphenyl). In certainembodiments, R^(1c) is phenyl, 3-fluorophenyl, 3-methylphenyl,4-chlorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, or4-ethylphenyl. In certain embodiments, R^(1c) is heteroaryl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(1c) is heterocyclyl.

In certain embodiments, R^(1b) and R^(1c) together with the N atom towhich they are attached independently form heteroaryl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(1b) and R^(1c) together with the N atom to which they are attachedindependently form heterocyclyl, optionally substituted with one or moresubstituents Q.

In certain embodiments, R^(1d) is hydrogen. In certain embodiments,R^(1d) is deuterium. In certain embodiments, R^(1d) is C₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1d) is C₂₋₆ alkenyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1d) is C₂₋₆ alkynyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1d) is C₃₋₇ cycloalkyl, optionally substituted with oneor more substituents Q. In certain embodiments, R^(1d) is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1d) is heteroaryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1d) is heterocyclyl,optionally substituted with one or more substituents Q.

In certain embodiments, R^(11a) is hydrogen. In certain embodiments,R^(11a) is deuterium.

In certain embodiments, R^(11b) is hydrogen. In certain embodiments,R^(11b) is deuterium.

In certain embodiments, R^(11c) is hydrogen. In certain embodiments,R^(11c) is deuterium.

In certain embodiments, R^(11d) is hydrogen. In certain embodiments,R^(11d) is deuterium.

In certain embodiments, R^(11e) is hydrogen. In certain embodiments,R^(11e) is deuterium.

In certain embodiments, R^(11f) is hydrogen. In certain embodiments,R^(11f) is deuterium.

In certain embodiments, R^(11a) and R^(11b) are deuterium. In certainembodiments, R^(11c) and R^(11d) are deuterium. In certain embodiments,R^(11e) and R^(11f) are deuterium.

In certain embodiments, at least one of R^(11a), R^(11b), R^(11c),R^(11d), R^(11e), and R^(11f) is deuterium. In certain embodiments, atleast two of R^(11a), R^(11b), R^(11c), R^(11d), R^(11e), and R^(11f)are deuterium. In certain embodiments, at least three of R^(11a),R^(11b), R^(11c), R^(11d), R^(11e), and R^(11f) are deuterium. Incertain embodiments, at least four of R^(11a), R^(11b), R^(11c),R^(11d), R^(11e), and R^(11f) are deuterium. In certain embodiments, atleast five of R^(11a), R^(11b), R^(11c), R^(11d), R^(11e), and R^(11f)are deuterium. In certain embodiments, at least six of R^(11a), R^(11b),R^(11c), R^(11d), R^(11e), and R^(11f) are deuterium. In certainembodiments, at least seven of R^(11a), R^(11b), R^(11c), R^(11d),R^(11e), and R^(11ff) are deuterium. In certain embodiments, R^(11a),R^(11b), R^(11c), R^(11d), R^(11e), and R^(11f) are deuterium.

In certain embodiments, a compound provided herein isdeuterium-enriched.

In certain embodiments, a compound provided herein is carbon-13enriched. In certain embodiments, a compound provided herein iscarbon-14 enriched. In certain embodiments, a compound provided hereincontains one or more less prevalent isotopes for other elements,including, but not limited to, ¹⁵N for nitrogen; ¹⁷O or ¹⁸O for oxygen,and ³³S, ³⁴S, or ³⁶S for sulfur.

In one embodiment, provided herein is a compound selected from:

Cmpd. R¹ R³ R⁵ R⁶ R⁷ R⁹ 1 D H H H H H 2 H D H H H H 3 H H D H H H 4 H HH D H H 5 H H H H D H 6 H H H H H D 7 D D H H H H 8 D H D H H H 9 D H HD H H 10 D H H H D H 11 D H H H H D 12 H D D H H H 13 H D H D H H 14 H DH H D H 15 H D H H H D 16 H H D D H H 17 H H D H D H 18 H H D H H H 19 HH H D D H 20 H H H D H D 21 H H H H D D 22 D D D H H H 23 D D D D H H 24D D D H D H 25 D D D H H D 26 D D D D D H 27 D D D D H D 28 D D D H D D29 H H H D D D 30 D H H D D D 31 H D H D D D 32 H H D D D D 33 D D H D DD 34 D H D D D D 35 H D D D D D 36 D D D D D Dand pharmaceutically acceptable salts, solvates, hydrates, and prodrugsthereof.

In another embodiment, provided herein is a compound selected from:

Cmpd. R¹ R³ R⁵ R⁶ R⁷ R⁹ R^(11a) R^(11b) R^(11c) R^(11d) R^(11e) R^(11f)51 H H H H H H D D H H H H 52 H H H H H H H H D D H H 53 H H H H H H H HH H D D 54 H H H H H H D D D D H H 55 H H H H H H D D H H D D 56 H H H HH H H H D D D D 57 H H H H H H D D D D D D 58 D D D H H H D D H H H H 59D D D H H H H H D D H H 60 D D D H H H H H H H D D 61 D D D H H H D D DD H H 62 D D D H H H D D H H D D 63 D D D H H H H H D D D D 64 D D D H HH D D D D D D 65 H H H D D D D D H H H H 66 H H H D D D H H D D H H 67 HH H D D D H H H H D D 68 H H H D D D D D D D H H 69 H H H D D D D D H HD D 70 H H H D D D H H D D D D 71 H H H D D D D D D D D D 72 D D D D D DD D H H H H 73 D D D D D D H H D D H H 74 D D D D D D H H H H D D 75 D DD D D D D D D D H H 76 D D D D D D D D H H D D 77 D D D D D D H H D D DD 78 D D D D D D D D D D D Dand pharmaceutically acceptable salts, solvates, hydrates, and prodrugsthereof.

In yet another embodiment, provided herein is4-(3,5-dichloro-2,4,6-trideuteriumphenoxy)-3-(3-oxo-piperazine-1-sulfonyl)-2,5,6-trideuteriumbenzonitrile,or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof.

In certain embodiments, a compound provided herein has an isotopicenrichment factor of no less than about 5, no less than about 10, noless than about 20, no less than about 30, no less than about 40, noless than about 50, no less than about 60, no less than about 70, noless than about 80, no less than about 90, no less than about 100, noless than about 200, no less than about 500, no less than about 1,000,no less than about 2,000, no less than about 5,000, or no less thanabout 10,000. In any events, however, an isotopic enrichment factor fora specified isotope is no greater than the maximum isotopic enrichmentfactor for the specified isotope, which is the isotopic enrichmentfactor when a compound at a given position is 100% enriched with thespecified isotope. Thus, the maximum isotopic enrichment factors aredifferent for different isotopes. The maximum isotopic enrichment factoris 6410 for deuterium and 90 for carbon-13.

In certain embodiments, a compound provided herein is deuteriumenriched. In certain embodiments, a compound provided herein has adeuterium enrichment factor of no less than about 64 (about 1% deuteriumenrichment), no less than about 130 (about 2% deuterium enrichment), noless than about 320 (about 5% deuterium enrichment), no less than about640 (about 10% deuterium enrichment), no less than about 1,300 (about20% deuterium enrichment), no less than about 3,200 (about 50% deuteriumenrichment), no less than about 4,800 (about 75% deuterium enrichment),no less than about 5,130 (about 80% deuterium enrichment), no less thanabout 5,450 (about 85% deuterium enrichment), no less than about 5,770(about 90% deuterium enrichment), no less than about 6,090 (about 95%deuterium enrichment), no less than about 6,220 (about 97% deuteriumenrichment), no less than about 6,280 (about 98% deuterium enrichment),no less than about 6,350 (about 99% deuterium enrichment), or no lessthan about 6,380 (about 99.5% deuterium enrichment). The deuteriumenrichment can be determined using conventional analytical methods knownto one of ordinary skill in the art, e.g., mass spectrometry or nuclearmagnetic resonance spectroscopy.

In certain embodiments, a compound provided herein is carbon-13enriched. In certain embodiments, the compound provided herein have acarbon-13 enrichment factor of no less than about 1.8 (about 2%carbon-13 enrichment), no less than about 4.5 (about 5% carbon-13enrichment), no less than about 9 (about 10% carbon-13 enrichment), noless than about 18 (about 20% carbon-13 enrichment), no less than about45 (about 50% carbon-13 enrichment), no less than about 68 (about 75%carbon-13 enrichment), no less than about 72 (about 80% carbon-13enrichment), no less than about 77 (about 85% carbon-13 enrichment), noless than about 81 (about 90% carbon-13 enrichment), no less than about86 (about 95% carbon-13 enrichment), no less than about 87 (about 97%carbon-13 enrichment), no less than about 88 (about 98% carbon-13enrichment), no less than about 89 (about 99% carbon-13 enrichment), orno less than about 90 (about 99.5% carbon-13 enrichment). The carbon-13enrichment can be determined using conventional analytical methods knownto one of ordinary skill in the art, e.g., mass spectrometry or nuclearmagnetic resonance spectroscopy.

In certain embodiments, at least one of the atoms of a compound providedherein, as specified as isotopically enriched, has isotopic enrichmentof no less than about 1%, no less than about 2%, no less than about 5%,no less than about 10%, no less than about 20%, no less than about 50%,no less than about 70%, no less than about 80%, no less than about 90%,or no less than about 98%. In certain embodiments, the atoms of acompound provided herein, as specified as isotopically enriched, haveisotopic enrichment of no less than about 1%, no less than about 2%, noless than about 5%, no less than about 10%, no less than about 20%, noless than about 50%, no less than about 70%, no less than about 80%, noless than about 90%, or no less than about 98%. In any events, theisotopic enrichment of each of the isotopically enriched atoms of acompound provided herein is no less than the natural abundance of theisotope specified.

In certain embodiments, at least one of the atoms of a compound providedherein, as specified as deuterium-enriched, has deuterium enrichment ofno less than about 1%, no less than about 2%, no less than about 5%, noless than about 10%, no less than about 20%, no less than about 50%, noless than about 70%, no less than about 80%, no less than about 90%, orno less than about 98%. In certain embodiments, the atoms of a compoundprovided herein, as specified as deuterium-enriched, have deuteriumenrichment of no less than about 1%, no less than about 2%, no less thanabout 5%, no less than about 10%, no less than about 20%, no less thanabout 50%, no less than about 70%, no less than about 80%, no less thanabout 90%, or no less than about 98%.

In certain embodiments, at least one of the atoms of a compound providedherein, as specified as ¹³C-enriched, has carbon-13 enrichment of noless than about 2%, no less than about 5%, no less than about 10%, noless than about 20%, no less than about 50%, no less than about 70%, noless than about 80%, no less than about 90%, or no less than about 98%.In certain embodiments, the atoms of a compound provided herein, asspecified as ¹³C-enriched, have carbon-13 enrichment of no less thanabout 1%, no less than about 2%, no less than about 5%, no less thanabout 10%, no less than about 20%, no less than about 50%, no less thanabout 70%, no less than about 80%, no less than about 90%, or no lessthan about 98%.

In certain embodiments, a compound provided herein is isolated orpurified. In certain embodiments, a compound provided herein has apurity of at least about 50%, at least about 70%, at least about 80%, atleast about 90%, at least about 95%, at least about 98%, at least about99%, or at least about 99.5% by weight.

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Wherethe compounds provided herein contain an alkenyl or alkenylene group,the compounds may exist as one or mixture of geometric cis/trans (orZ/E) isomers. Where structural isomers are interconvertible, thecompounds may exist as a single tautomer or a mixture of tautomers. Thiscan take the form of proton tautomerism in the compounds that contain,for example, an imino, keto, or oxime group; or so-called valencetautomerism in the compounds that contain an aromatic moiety. It followsthat a single compound may exhibit more than one type of isomerism.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. As such, oneof skill in the art will recognize that administration of a compound inits (R) form is equivalent, for compounds that undergo epimerization invivo, to administration of the compound in its (S) form. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude synthesis from a suitable optically pure precursor, asymmetricsynthesis from achiral starting materials, or resolution of anenantiomeric mixture, for example, chiral chromatography,recrystallization, resolution, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation.

When the compounds provided herein contain an acidic or basic moiety,they each may also be provided as a pharmaceutically acceptable salt(See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook ofPharmaceutical Salts, Properties, and Use,” Stahl and Wermuth, Ed.;Wiley-VCH and VHCA, Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

In one embodiment, the compounds provided herein are a hydrochloridesalt.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

A compound provided herein provided herein may also be provided as aprodrug, which is a functional derivative of the compound, for example,a compound of Formula I, and is readily convertible into the parentcompound in vivo. Prodrugs are often useful because, in some situations,they may be easier to administer than their parent compound. They may,for instance, be bioavailable by oral administration whereas the parentcompound is not. The prodrugs may also have enhanced solubility inpharmaceutical compositions over the parent compound. A prodrug may beconverted into the parent drug by various mechanisms, includingenzymatic processes and metabolic hydrolysis. See Harper, Progress inDrug Research 1962, 4, 221-294; Morozowich et al. in “Design ofBiopharmaceutical Properties through Prodrugs and Analogs,” Roche Ed.,APHA Acad. Pharm. Sci. 1977; “Bioreversible Carriers in Drug in DrugDesign, Theory and Application,” Roche Ed., APHA Acad. Pharm. Sci. 1987;“Design of Prodrugs,” Bundgaard, Elsevier, 1985; Wang et al., Curr.Pharm. Design 1999, 5, 265-287; Pauletti et al., Adv. Drug. DeliveryRev. 1997, 27, 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365;Gaignault et al., Pract. Med. Chem. 1996, 671-696; Asghamejad in“Transport Processes in Pharmaceutical Systems,” Amidon et al., Ed.,Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab.Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug DeliveryRev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12;Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled DrugDelivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8,1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130;Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al.,J. Pharm. Sci. 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem.Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4,49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977,409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu andThakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151;Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino andBorchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv.Drug Delivery Rev. 1999, 39, 63-80; and Waller et al., Br. J. Clin.Pharmac. 1989, 28, 497-507.

Methods of Synthesis

The compounds provided herein can be prepared, isolated, or obtained byany method known to one of skill in the art. For an example, a compoundof Formula I can be prepared according to the methods described inInternational Pat. App. Pub. Nos.: WO 2003/022277 and WO 2004/084898;and U.S. Pat. App. Pub. Nos.: US 2010/0273782, US 2010/0273785, US2010/0273795, and US 2011/0218207; the disclosure of each of which isincorporated herein by reference in its entirety.

In one embodiment, an isotope is introduced into a compound providedherein by synthetic techniques that employ suitable isotopicallyenriched reagents, whereby isotopic enrichment is pre-determined. Inanother embodiment, an isotope is introduced into a compound providedherein by exchange techniques, wherein isotopic enrichment is determinedby equilibrium conditions, which may be highly variable depending on thereaction conditions. In yet another embodiment, deuterium is introducedinto a compound provided herein by direct deuteration.

In certain embodiments, deuterium is incorporated synthetically into oneor more positions of a compound of Formula I, according to the syntheticprocedures as shown in Scheme I, using appropriate deuterated startingmaterials or intermediates. In general, compound A1 reacts with compoundA2 via a nucleophilic aromatic substitution reaction to form compound A3with the release of hydrochloride. The nitro group of compound A3 isreduced to an amino group with a reducing reagent, e.g., sodiumhydrosulfite or tin (II) chloride, to form analine A4, which issubsequently converted into sulfonyl chloride A5 via the Sandmeyerreaction. Compound A5 is then coupled with amine A6 to form a compoundof Formula I.

In one embodiment, to introduce deuterium at one or more positions orgroups of R¹, R², R³, R⁴, and R⁵, compound A2 with the correspondingdeuterium is coupled with compound A1 via a nucleophilic aromaticsubstitution reaction to form compound A3 with the release ofhydrochloride. In another embodiment, to introduce deuterium at one ormore positions or groups of R⁶, R⁷, R⁸, and R⁹, nitrobenzene A1 with thecorresponding deuterium substitutions is coupled with compound A2 via anucleophilic aromatic substitution reaction to form deuterated compoundA3. In yet another embodiment, to introduce deuterium at one or morepositions or groups of the R¹¹ groups, compound A6 with thecorresponding deuterium is coupled with sulfonyl chloride A5 to form adeuterated compound of Formula I.

The deuterated starting materials and intermediates used herein areeither commercially available, or can be prepared by methods known toone of skill in the art or by following procedures similar to thosedescribed herein in the Example section and routine modificationsthereof.

In certain embodiments, deuterium is also incorporated to variouspositions of a compound of Formula I, which has an exchangeable proton,such as amine or amide N—H and hydroxyl O—H, via proton-deuteriumequilibrium exchange.

Additional examples of the syntheses of deuterium-enriched and/orcarbon-13 enriched compounds of Formula I are illustrated in Schemes IIand III.

Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising a compoundprovided herein, e.g., a compound of Formula I, or an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;and a pharmaceutically acceptable excipient.

A compound provided herein may be administered alone, or in combinationwith one or more other compounds provided herein. The pharmaceuticalcompositions that comprise a compound provided herein, e.g., a compoundof Formula I, can be formulated in various dosage forms for oral,parenteral, and topical administration. The pharmaceutical compositionscan also be formulated as modified release dosage forms, includingdelayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-,accelerated-, fast-, targeted-, programmed-release, and gastricretention dosage forms. These dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra;Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et al.,Eds., Marcel Dekker, Inc.: New York, N.Y., 2008).

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a compound providedherein, e.g., a compound of Formula I, or an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, or amixture of two or more tautomers thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; and one or morepharmaceutically acceptable excipients.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise a compoundprovided herein, e.g., a compound of Formula I, or an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;and one or more pharmaceutically acceptable excipients.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, e.g., a compound of Formula I, or an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;and one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions provided herein can be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to physically discrete a unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of an activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet and capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofa multiple-dosage form include a vial, bottle of tablets or capsules, orbottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered atonce or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

A. Oral Administration

The pharmaceutical compositions provided herein for oral administrationcan be provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), the pharmaceutical compositions can contain one ormore pharmaceutically acceptable carriers or excipients, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in the pharmaceutical compositions provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The amount of a disintegrant in the pharmaceutical compositionsprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art. The pharmaceuticalcompositions provided herein may contain from about 0.5 to about 15% orfrom about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl) acetal ofa lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-3-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When the pharmaceutical compositions provided herein are formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungistatic concentrations. All parenteral formulations must be sterile,as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical compositions are provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical compositions are provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical compositions are provided as sterile dry insolubleproducts to be reconstituted with a vehicle prior to use. In stillanother embodiment, the pharmaceutical compositions are provided asready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, the pharmaceutical compositions provided herein aredispersed in a solid inner matrix, which is surrounded by an outerpolymeric membrane that is insoluble in body fluids but allows theactive ingredient in the pharmaceutical compositions diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereincan also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions can also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable creamvehicles may be water-washable, and contain an oil phase, an emulsifier,and an aqueous phase. The oil phase is also called the “internal” phase,which is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation may be a nonionic,anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include, but are not limitedto, crosslinked acrylic acid polymers, such as carbomers,carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, andpolyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

The pharmaceutical compositions provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, and polyacrylic acid. Combinations of the various vehiclescan also be used. Rectal and vaginal suppositories may be prepared bycompressing or molding. The typical weight of a rectal and vaginalsuppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein can be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions can be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein; a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as 1-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include, but are notlimited to, dextran, glucose, maltose, sorbitol, xylitol, fructose,sucrose, and trehalose. The pharmaceutical compositions provided hereinfor inhaled/intranasal administration can further comprise a suitableflavor, such as menthol and levomenthol; and/or sweeteners, such assaccharin and saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration can be formulated to be immediate release or modifiedrelease, including delayed-, sustained-pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include, but are not limited to, delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al. in “Encyclopediaof Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In certain embodiments, the pharmaceutical compositions provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc.,Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated with a non-erodible matrix device. The activeingredient(s) is dissolved or dispersed in an inert matrix and isreleased primarily by diffusion through the inert matrix onceadministered. Materials suitable for use as a non-erodible matrix deviceinclude, but are not limited to, insoluble plastics, such aspolyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethyleneand propylene, ionomer polyethylene terephthalate, butyl rubbers,epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including, but not limited to, one-chamber system, two-chambersystem, asymmetric membrane technology (AMT), and extruding core system(ECS). In general, such devices have at least two components: (a) a corewhich contains an active ingredient; and (b) a semipermeable membranewith at least one delivery port, which encapsulates the core. Thesemipermeable membrane controls the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusionthrough the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents is water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels.”Suitable water-swellable hydrophilic polymers as osmotic agents include,but are not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate device or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein can also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, those disclosed in U.S. Pat. Nos. 6,316,652;6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751;6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307;5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

Methods of Use

In one embodiment, provided herein is a method of treating, preventing,or ameliorating one or more symptoms of a CCR3-mediated disease,disorder, or condition in a subject, which comprises administering tothe subject a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula I, or an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, or amixture of two or more tautomers thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.

In another embodiment, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of a disease, disorder,or condition associated with CCR3 in a subject, which comprisesadministering to the subject a therapeutically effective amount of acompound provided herein, e.g., a compound of Formula I, or anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof.

In yet another embodiments, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of a disease, disorder,or condition responsive to the modulation of CCR3 activity in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein, e.g., a compound of Formula I, oran enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof.

In yet another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of aneosinophil-related disease, disorder, or condition in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein, e.g., a compound of Formula I, oran enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof.

In yet another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of a basophil-relateddisease, disorder, or condition in a subject, comprising administeringto a subject, a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula I, or an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, or amixture of two or more tautomers thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.

In yet another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of a mast cell-relateddisease, disorder, or condition in a subject, comprising administeringto a subject a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula I, or an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, or amixture of two or more tautomers thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.

In still another embodiment, provided is a method for treating,preventing, or ameliorating one or more symptoms of an inflammatorydisease in a subject, comprising administering to the subject atherapeutically effective amount of a compound provided herein, e.g., acompound of Formula I, or an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, a tautomer, or a mixture of two ormore tautomers thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof.

In one embodiment, the subject is a mammal. In another embodiment, thesubject is a human.

The diseases, disorders, or conditions treatable with a compoundprovided herein, e.g., a compound of Formula I, or an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,include, but are not limited to, (1) inflammatory or allergic diseases,including systemic anaphylaxis and hypersensitivity disorders, atopicdermatitis, urticaria, drug allergies, insect sting allergies, foodallergies (including celiac disease), and mastocytosis; (2) inflammatorybowel diseases, including Crohn's disease, ulcerative colitis, ileitis,and enteritis; (3) vasculitis, and Behcet's syndrome; (4) psoriasis andinflammatory dermatoses, including dermatitis, eczema, atopicdermatitis, allergic contact dermatitis, urticaria, viral cutaneouspathologies including those derived from human papillomavirus, HIV orRLV infection, bacterial, flugal, and other parasital cutaneouspathologies, and cutaneous lupus erythematosus; (5) asthma andrespiratory allergic diseases, including allergic asthma, exerciseinduced asthma, allergic rhinitis, otitis media, allergicconjunctivitis, hypersensitivity lung diseases, and chronic obstructivepulmonary disease; (6) autoimmune diseases, including arthritis(including rheumatoid and psoriatic), systemic lupus erythematosus, typeI diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, andglomerulonephritis; (7) graft rejection (including allograft rejectionand graft-v-host disease), e.g., skin graft rejection, solid organtransplant rejection, and bone marrow transplant rejection; (8) fever;(9) cardiovascular disorders, including acute heart failure,hypotension, hypertension, angina pectoris, myocardial infarction,cardiomyopathy, congestive heart failure, atherosclerosis, coronaryartery disease, restenosis, and vascular stenosis; (10) cerebrovasculardisorders, including traumatic brain injury, stroke, ischemicreperfusion injury and aneurysm; (11) cancers of the breast, skin,prostate, cervix, uterus, ovary, testes, bladder, lung, liver, larynx,oral cavity, colon and gastrointestinal tract (e.g., esophagus, stomach,pancreas), brain, thyroid, blood, and lymphatic system; (12) fibrosis,connective tissue disease, and sarcoidosis, (13) genital andreproductive conditions, including erectile dysfunction; (14)gastrointestinal disorders, including gastritis, ulcers, nausea,pancreatitis, and vomiting; (15) neurologic disorders, includingAlzheimer's disease; (16) sleep disorders, including insomnia,narcolepsy, sleep apnea syndrome, and Pickwick Syndrome; (17) pain; (18)renal disorders; (19) ocular disorders, including glaucoma; and (20)infectious diseases, including HIV.

In certain embodiments, the disease, disorder, or condition is selectedfrom the group consisting of asthma, allergic asthma, exercise inducedasthma, allergic rhinitis, perennial allergic rhinitis, seasonalallergic rhinitis, atopic dermatitis, contact hypersensitivity, contactdermatitis, conjunctivitis, allergic conjunctivitis, eosinophilicbronchitis, food allergies, eosinophilic gastroenteritis, inflammatorybowel disease, ulcerative colitis, Crohn's disease, mastocytosis, hyperIgE syndrome, systemic lupus erythematous, psoriasis, acne, multiplesclerosis, allograft rejection, reperfusion injury, Churg-Strausssyndrome, sinusitis, basophilic leukemia, chronic urticaria, basophilicleukocytosis, eczema, COPD (chronic obstructive pulmonary disorder),arthritis, rheumatoid arthritis, psoriatic arthritis, andosteoarthritis.

In certain embodiments, the disease, disorder, or condition is asthma,exercise induced asthma, allergic rhinitis, atopic dermatitis, COPD, orallergic conjunctivitis.

Depending on the disease, disorder, or condition to be treated, and thesubject's condition, the compounds or pharmaceutical compositionsprovided herein can be administered by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracistemalinjection or infusion, subcutaneous injection, or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal orlocal) routes of administration and can be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants, and vehicles appropriate for each routeof administration. Also provided is administration of the compounds orpharmaceutical compositions provided herein in a depot formulation, inwhich the active ingredient is released over a predefined time period.

In the treatment, prevention, or amelioration of one or more symptoms ofasthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever,sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis,multiple sclerosis, atherosclerosis, transplant rejection, inflammatorybowel disease, cancer, or other conditions, disorders or diseasesassociated with a CCR3 receptor, an appropriate dosage level generallyis ranging from about 0.001 to 100 mg/kg/day, from about 0.01 to about75 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.5 toabout 25 mg/kg/day, or from about 1 to about 20 mg/kg/day, which can beadministered in single or multiple doses. Within this range, the dosagecan be ranging from about 0.005 to about 0.05, from about 0.05 to about0.5, from about 0.5 to about 5.0, from about 1 to about 15, from about 1to about 20, or from about 1 to about 50 mg/kg/day. In certainembodiments, the dosage level is ranging from about 0.001 to about 100mg/kg/day. In certain embodiments, the dosage level is ranging fromabout 0.01 to about 75 mg/kg/day. In certain embodiments, the dosagelevel is ranging from about 0.1 to about 50 mg/kg/day. In certainembodiments, the dosage level is ranging from about 0.5 to about 25mg/kg/day. In certain embodiments, the dosage level is ranging fromabout 1 to about 20 mg/kg/day.

For oral administration, the pharmaceutical compositions provided hereincan be formulated in the form of tablets containing from about 1.0 toabout 1,000 mg of the active ingredient, in one embodiment, about 1,about 5, about 10, about 15, about 20, about 25, about 50, about 75,about 100, about 150, about 200, about 250, about 300, about 400, about500, about 600, about 750, about 800, about 900, and about 1,000 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The pharmaceutical compositions can beadministered on a regimen of 1 to 4 times per day, including once,twice, three times, and four times per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient can be varied and willdepend upon a variety of factors, including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

In one embodiment, provided herein is a method of modulating CCR3activity, comprising contacting a CCR3 receptor with a compound providedherein, e.g., a compound of Formula I, or an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, or amixture of two or more tautomers thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. In oneembodiment, the CCR3 receptor is expressed by a cell.

The compounds provided herein, e.g., a compound of Formula I, or anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof, can also be combined or used in combination with otheragents useful in the treatment, prevention, or amelioration of one ormore symptoms of the disorders, diseases, or conditions for which thecompounds provided herein are useful, including asthma, allergicrhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemiclupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis,atherosclerosis, transplant rejection, inflammatory bowel disease,cancer, infectious diseases, and those pathologies noted above.

In certain embodiments, a compound provided herein can be combined withone or more steroidal drugs known in the art, including, but not limitedto, aldosterone, beclometasone, betamethasone, deoxycorticosteroneacetate, fludrocortisone, hydrocortisone (cortisol), prednisolone,prednisone, methylprednisolone, dexamethasone, and triamcinolone.

In certain embodiments, a compound provided herein can be combined withone or more antibacterial agents known in the art, including, but notlimited to, amikacin, amoxicillin, ampicillin, arsphenamine,azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin,cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir,cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin,cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin,clarithromycin, clindamycin, cloxacillin, colistin, dalfopristin,demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin,enrofloxacin, ertepenem, ethambutol, flucloxacillin, fosfomycin,furazolidone, gatifloxacin, geldanamycin, gentamicin, herbimycin,imipenem, isoniazid, kanamycin, levofloxacin, linezolid, lomefloxacin,loracarbef, mafenide, moxifloxacin, meropenem, metronidazole,mezlocillin, minocycline, mupirocin, nafcillin, neomycin, netilmicin,nitrofurantoin, norfloxacin, ofloxacin, oxytetracycline, penicillin,piperacillin, platensimycin, polymyxin B, prontocil, pyrazinamide,quinupristine, rifampin, roxithromycin, spectinomycin, streptomycin,sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin,telithromycin, tetracycline, ticarcillin, tobramycin, trimethoprim,troleandomycin, trovafloxacin, and vancomycin.

In certain embodiments, a compound provided herein can be combined withone or more antifungal agents known in the art, including, but notlimited to, amorolfine, amphotericin B, anidulafungin, bifonazole,butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole,econazole, fenticonazole, filipin, fluconazole, isoconazole,itraconazole, ketoconazole, micafungin, miconazole, naftifine,natamycin, nystatin, oxyconazole, ravuconazole, posaconazole, rimocidin,sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, andvoriconazole.

In certain embodiments, a compound provided herein can be combined withone or more anticoagulants known in the art, including, but not limitedto, acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux,heparin, phenindione, warfarin, and ximelagatran.

In certain embodiments, a compound provided herein can be combined withone or more thrombolytics known in the art, including, but not limitedto, anistreplase, reteplase, t-PA (alteplase activase), streptokinase,tenecteplase, and urokinase.

In certain embodiments, a compound provided herein can be combined withone or more non-steroidal anti-inflammatory agents known in the art,including, but not limited to, aceclofenac, acemetacin, amoxiprin,aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib,choline magnesium salicylate, diclofenac, diflunisal, etodolac,etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen,indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib,meclofenamic acid, mefenamic acid, meloxicam, metamizole, methylsalicylate, magnesium salicylate, nabumetone, naproxen, nimesulide,oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicylsalicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenicacid, and tolmetin.

In certain embodiments, a compound provided herein can be combined withone or more antiplatelet agents known in the art, including, but notlimited to, abciximab, cilostazol, clopidogrel, dipyridamole,ticlopidine, and tirofibin.

A compound provided herein can also be administered in combination withother classes of compounds, including, but not limited to, (1)alpha-adrenergic agents; (2) antiarrhythmic agents; (3)anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics,such as anthracyclines, bleomycins, mitomycin, dactinomycin, andplicamycin; (5) anticancer agents and cytotoxic agents, e.g., alkylatingagents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas,ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol,argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione,warfarin, and ximelagatran; (7) anti-diabetic agents, such as biguanides(e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g., troglitazone,rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8)antifungal agents, such as amorolfine, amphotericin B, anidulafungin,bifonazole, butenafine, butoconazole, caspofungin, ciclopirox,clotrimazole, econazole, fenticonazole, filipin, fluconazole,isoconazole, itraconazole, ketoconazole, micafungin, miconazole,naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole,rimocidin, sertaconazole, sulconazole, terbinafine, terconazole,tioconazole, and voriconazole; (9) antiinflammatories, e.g.,non-steroidal anti-inflammatory agents, such as aceclofenac, acemetacin,amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen,celecoxib, choline magnesium salicylate, diclofenac, diflunisal,etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen,ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen,lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole,methyl salicylate, magnesium salicylate, nabumetone, naproxen,nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam,salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam,tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folateantagonists, purine analogues, and pyrimidine analogues; (11)anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab,eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel,ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12)antiproliferatives, such as methotrexate, FK506 (tacrolimus), andmycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor,such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors;(15) beta-adrenergic agents, such as carvedilol and metoprolol; (16)bile acid sequestrants, such as questran; (17) calcium channel blockers,such as amlodipine besylate; (18) chemotherapeutic agents; (19)cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib;(20) cyclosporins; (21) cytotoxic drugs, such as azathioprine andcyclophosphamide; (22) diuretics, such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzothiazide, ethacrynic acid, ticrynafen,chlorthalidone, furosenide, muzolimine, bumetanide, triamterene,amiloride, and spironolactone; (23) endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; (24) enzymes, such asL-asparaginase; (25) Factor VIIa Inhibitors and Factor Xa Inhibitors;(26) famesyl-protein transferase inhibitors; (27) fibrates; (28) growthfactor inhibitors, such as modulators of PDGF activity; (29) growthhormone secretagogues; (30) HMG CoA reductase inhibitors, such aspravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a.itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known asrosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP)inhibitors; (31) hormonal agents, such as glucocorticoids (e.g.,cortisone), estrogens/antiestrogens, androgens/antiandrogens,progestins, and luteinizing hormone-releasing hormone antagonists, andoctreotide acetate; (32) immunosuppressants; (33) mineralocorticoidreceptor antagonists, such as spironolactone and eplerenone; (34)microtubule-disruptor agents, such as ecteinascidins; (35)microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; (36) MTP Inhibitors; (37) niacin; (38)phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); (39) plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF)antagonists; (41) platinum coordination complexes, such as cisplatin,satraplatin, and carboplatin; (42) potassium channel openers; (43)prenyl-protein transferase inhibitors; (44) protein tyrosine kinaseinhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors;(47) steroids, such as aldosterone, beclometasone, betamethasone,deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol),prednisolone, prednisone, methylprednisolone, dexamethasone, andtriamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombininhibitors, such as hirudin; (50) thrombolytic agents, such asanistreplase, reteplase, tenecteplase, tissue plasminogen activator(tPA), recombinant tPA, streptokinase, urokinase, prourokinase, andanisoylated plasminogen streptokinase activator complex (APSAC); (51)thromboxane receptor antagonists, such as ifetroban; (52) topoisomeraseinhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors),such as omapatrilat and gemopatrilat; and (54) other miscellaneousagents, such as, hydroxyurea, procarbazine, mitotane,hexamethylmelamine, and gold compounds.

Such other agents, or drugs, can be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with acompound provided herein, e.g., a compound of Formula I, or a singleenantiomer, a mixture of enantiomers, or a mixture of diastereomersthereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof. When a compound provided herein is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound provided herein can be utilized,but is not required. Accordingly, the pharmaceutical compositionsprovided herein include those that also contain one or more other activeingredients or therapeutic agents, in addition to a compound providedherein.

The weight ratio of a compound provided herein to the second activeingredient can be varied, and will depend upon the effective dose ofeach ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound provided herein is combined with aNSAID, the weight ratio of the compound to the NSAID can range fromabout 1,000:1 to about 1:1,000, or about 200:1 to about 1:200.Combinations of a compound provided herein and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

The compounds provided herein can also be provided as an article ofmanufacture using packaging materials well known to those of skill inthe art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment.

Provided herein also are kits which, when used by a medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes a container and a dosage form of a compoundprovided herein, e.g., a compound of Formula I, or a single enantiomer,a mixture of enantiomers, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof.

In certain embodiments, the kit includes a container comprising a dosageform of a compound provided herein, e.g., a compound of Formula I, or asingle enantiomer, a mixture of enantiomers, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof, in a container comprising one or more othertherapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredient(s). Examples of such devices include,but are not limited to, syringes, needle-less injectors drip bags,patches, and inhalers. The kits provided herein can also include condomsfor administration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar); Hz(Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min(minutes); HPLC (high pressure liquid chromatography); THF(tetrahydrofuran); and DMSO-d₆ (deuterated dimethylsulfoxide).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions are conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify applicable chemistry through the use of specific examplesand are not indicative of the scope of the disclosure.

Example 1 Preparation of4-(3,5-dichloro-2,4,6-trideuteriumphenoxy)-3-(3-oxo-piperazine-1-sulfonyl)-2,5,6-trideuteriumbenzonitrile36

4-(3,5-Dichloro-2,4,6-trideuteriumphenoxy)-3-(3-oxo-piperazine-1-sulfonyl)-2,5,6-trideuteriumbenzonitrile36 was synthesized as shown in Scheme 1.

Preparation of 4-chloro-2,3,6-trideuterium-5-nitrobenzonitrile B2. To asolution of 4-chlorobenzonitrile-d₄ B1 (2.00 g, 14.13 mmol) in fumingnitric acid (26 mL) in an ice bath was added dropwise sulfuric acid (20mL) over 90 min. After stirred for additional 2 hrs, the reactionmixture was poured into ice water (500 mL). The resulting whiteprecipitate was collected by filtration and dried to yield4-chloro-2,3,6-trideuterium-5-nitrobenzonitrile B2 as a white solid(2.27 g, 100% purity, 86.9% yield).

Preparation of4-(3,5-dichloro-2,4,6-trideuteriumphenoxy)-2,5,6-trideuterium-3-nitrobenzonitrileB3. To a solution of 4-chloro-2,3,6-trideuterium-5-nitrobenzonitrile B2(92.2 mg, 0.56 mmol) in THF (4 mL) were added potassium carbonate (232mg) and 3,5-dichloro-2,4,6-trideuteriumphenol (104 mg, 0.56 mmol). Thereaction mixture was refluxed at 70° C. overnight. The reaction mixturewas diluted with EtOAc and filtered. The EtOAc solution was concentratedand then treated with hexanes. The resulting solid was filtered anddried to yield4-(3,5-dichloro-2,4,6-trideuteriumphenoxy)-2,5,6-trideuterium-3-nitrobenzonitrileB3 as a yellow powder (147 mg, 100% purity, 83.3% yield).

Preparation of3,5-dichloro-2,4,6-trideuteriumphenoxy)-3-amino-2,5,6-trideuteriumbenzonitrileB4. To a solution of tin(II) chloride (216 mg, 1.14 mmol) in conc. HCl(38 μL) and ethanol (10 mL) was added4-(3,5-dichloro-2,4,6-trideuteriumphenoxy)-2,5,6-trideuterium-3-nitrobenzonitrileB3 (120 mg, 0.38 mmol) slowly at 70° C. The reaction mixture wasrefluxed overnight and then poured into ice water. The resultingprecipitate was collected by filtration to yield3,5-dichloro-2,4,6-trideuteriumphenoxy)-3-amino-2,5,6-trideuteriumbenzonitrileB4 (98 mg, 85.2% purity, 90.5% yield).

Preparation of2-(3,5-dichloro-2,4,6-trideuteriumphenoxy)-3,4,6-trideuterium-5-cyanobenzene-1-sulfonylchloride B5. A saturated SO₂ solution in glacial acid was prepared bybubbling SO₂ into glacial acetic acid (2 mL) until no further change inmass was observed (about 0.5 hrs). A reaction mixture was prepared bygrounding3,5-dichloro-2,4,6-trideuteriumphenoxy)-3-amino-2,5,6-trideuteriumbenzonitrileB4 (98 mg, 0.34 mmol) into fine powder and adding the grounded compoundin one portion to a mixture of conc. aqueous HCl (0.5 mL) and glacialacetic acid (0.5 mL). After white precipitates appeared, the reactionmixture was cooled to at least −10° C. in a dry-ice-ethanol bath whilestirring. Sodium nitrite (26 mg, 0.37 mmol) dissolved in minimal waterwas added dropwise to the reaction mixture, such that the temperaturedid not exceed −5° C. After all the sodium nitrile was added, themixture was stirred at a temperature below −5° C. for 30 min. In themeantime, copper (I) chloride (3 mg, 0.03 mmol) and copper (II) chloridedihydrate (15 mg, 0.09 mmol) were added to the saturated SO₂ solutionand the resulting solution was stirred for 15 min. The saturated SO₂solution was then cooled to 10 OC in an ice bath. The diazonium in thereaction mixture was added in portions to the saturated SO₂ solution,such that the temperature did not exceed 30° C. After all the diazoniumwas added, the solution was stirred for 30 min, or until gas evolutionceased, forming a green solution. The solution was poured into 100 mL ofice water with stirring over the course of 5 min. The mixture wasfiltered, washed with copious water, and tried overnight in vacuum toyield2-(3,5-dichloro-2,4,6-trideuteriumphenoxy)-3,4,6-trideuterium-5-cyanobenzene-1-sulfonylchloride B5 as a yellow powder (91 mg, 90% purity, 73% yield).

Preparation of4-(3,5-dichloro-2,4,6-trideuteriumphenoxy)-3-(3-oxo-piperazine-1-sulfonyl)-2,5,6-trideuteriumbenzonitrile36. To a solution of2-(3,5-dichloro-2,4,6-trideuteriumphenoxy)-3,4,6-trideuterium-5-cyanobenzene-1-sulfonylchloride B5 (90.6 mg, 0.25 mmol) in THF (4 mL) was added 2-oxopiperazine(25 mg, 0.25 mmol). After the mixture was sonicated, triethylamine (25mg, 0.25 mmol) was then added and the reaction mixture was stirred atroom temperature until completion as determined by HPLC. The reactionmixture was filtered and concentrated. The resulting residue wasredissolved in THF. The mixture was heated in 30% MeOH/H₂O to form aslurry, which was filtered to yield4-(3,5-dichloro-2,4,6-trideuteriumphenoxy)-3-(3-oxo-piperazine-1-sulfonyl)-2,5,6-trideuteriumbenzonitrile36 as an off-white solid (72 mg, 97.8% purity, 67% yield). Meltingpoint: 207-210° C. ¹H NMR (500 MHz, DMSO-D₆) δ 9.54 (br, 1H), 3.81 (s,2H), 3.52 (t, J1=J2=6 Hz, 2H), 3.11 (m, 2H).

Example 2 Pharmacokinetic Studies

Pharmacokinetic properties of4-(3,5-dichloro-2,4,6-trideuteriumphenoxy)-3-(3-oxo-piperazine-1-sulfonyl)-2,5,6-trideuteriumbenzonitrile36 and4-(3,5-dichlorophenoxy)-3-(3-oxo-piperazine-1-sulfonyl)benzonitrile C1were determined using rats. Animals were randomized into two groups,each having 3 rats.4-(3,5-Dichloro-2,4,6-trideuteriumphenoxy)-3-(3-oxo-piperazine-1-sulfonyl)-2,5,6-trideuteriumbenzonitrile36 and4-(3,5-dichlorophenoxy)-3-(3-oxo-piperazine-1-sulfonyl)benzonitrile C1were administered at 3 mg/kg in EtOH/Solutol/H₂O formulations.Pharmacokinetic parameters of4-(3,5-dichloro-2,4,6-trideuteriumphenoxy)-3-(3-oxo-piperazine-1-sulfonyl)-2,5,6-trideuteriumbenzonitrile36 and4-(3,5-dichlorophenoxy)-3-(3-oxo-piperazine-1-sulfonyl)benzonitrile C1are summarized in Table 2.4-(3,5-dichlorophenoxy)-3-(3-oxo-piperazine-1-sulfonyl)benzonitrile C1was synthesized according to the procedure as described in U.S. Pat.App. Pub. No.: US 2011/0218207, the disclosure of which is incorporatedherein by reference in its entirety.

TABLE 2 Compound C1 Compound 36 Cmpd # Rat 1 Rat 2 Rat 3 Rat 1 Rat 2 Rat3 C_(max) (ng/mL) 34.4 65.8 59.9 166.0 46.3 128.0 T_(max) (hr) 2.0 4.02.0 2.0 4.0 0.3 Half-life (hr) 5.517 3.720 4.045 3.296 1.122 1.515 AUC199.7 449.8 317.4 819.8 271.7 489.8 (μg · hr/L) AUC_(norm) 66.6 149.9105.8 273.3 90.6 163.3 (μg · hr/L)

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. An isotopically enriched compound of Formula II:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt thereof; wherein: R¹, R²,R³, R⁴, and R⁵, are each independently hydrogen, deuterium, halo, orC₁₋₆ alkyl; R⁶, R⁷, and R⁹ are each independently hydrogen or deuterium;R⁸ is cyano or nitro; R¹⁰ is (a) hydrogen; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c),or —S(O)₂NR^(1b)R^(1c); R^(11a), R^(11b), R^(11c), R^(11d), R^(11e), andR^(11f) are each independently hydrogen or deuterium; X is O or S;wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,heterocyclyl, and heteroaryl is optionally substituted with one or moresubstituents Q, where each Q is independently selected from (a)deuterium, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more substituents Q^(a); and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen ordeuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, each optionallysubstituted with one or more substituents Q^(a); or (iii) each pair ofR^(b) and R^(c) together with the N atom to which they are attached formheterocyclyl, optionally substituted with one or more substituentsQ^(a); wherein each Q^(a) is independently selected from the groupconsisting of (a) deuterium, cyano, halo, and nitro; (b) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen ordeuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) eachpair of R^(f) and R^(g) together with the N atom to which they areattached form heterocyclyl.
 2. The compound of claim 1, wherein R^(11a)and R^(11b) are hydrogen.
 3. The compound of claim 1, wherein R^(11a)and R^(11b) are deuterium.
 4. The compound of claim 1, wherein R^(11c)and R^(11d) are hydrogen.
 5. The compound of claim 1, wherein R^(11c)and R^(11d) are deuterium.
 6. The compound of claim 1, wherein R^(11e)and R^(11f) are hydrogen.
 7. The compound of claim 1, wherein R^(11e)and R^(11f) are deuterium.
 8. The compound of claim 1, wherein two ofR¹, R², R³, R⁴, and R⁵ are halo or C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q; and the remaining three are hydrogen ordeuterium.
 9. The compound of claim 8, wherein two of R¹, R², R³, R⁴,and R⁵ are chloro, methyl, —CH₂D, —CHD₂, or -CD₃; and the remainingthree are hydrogen or deuterium.
 10. The compound of claim 1, wherein R¹is hydrogen.
 11. The compound of claim 1, wherein R¹ is deuterium. 12.The compound of claim 1, wherein R² is chloro.
 13. The compound of claim1, wherein R² is methyl, —CH₂D, —CHD₂, or -CD₃.
 14. The compound ofclaim 1, wherein R¹ is chloro.
 15. The compound of claim 1, wherein R¹is methyl, —CH₂D, —CHD₂, or -CD₃.
 16. The compound of claim 1, whereinR² is hydrogen.
 17. The compound of claim 1, wherein R² is deuterium.18. The compound of claim 1, wherein R⁴ is chloro.
 19. The compound ofclaim 1, wherein R⁴ is methyl, —CH₂D, —CHD₂, or -CD₃.
 20. The compoundof claim 1, wherein R³ is hydrogen.
 21. The compound of claim 1, whereinR³ is deuterium.
 22. The compound of claim 1, wherein R⁵ is hydrogen.23. The compound of claim 1, wherein R⁵ is deuterium.
 24. The compoundof claim 1, wherein R⁶ is hydrogen.
 25. The compound of claim 1, whereinR⁶ is deuterium.
 26. The compound of claim 1, wherein R⁷ is hydrogen.27. The compound of claim 1, wherein R⁷ is deuterium.
 28. The compoundof claim 1, wherein R⁹ hydrogen.
 29. The compound of claim 1, wherein R⁹is deuterium.
 30. The compound of claim 1, wherein R⁸ is cyano.
 31. Thecompound of claim 1, wherein R⁸ is —¹³CN.
 32. The compound of claim 1,wherein R⁸ is nitro.
 33. The compound of claim 1, wherein R¹⁰ ishydrogen.
 34. The compound of claim 1, wherein R¹⁰ is deuterium.
 35. Thecompound of claim 1, wherein X is O.
 36. The compound of claim 1,wherein X is S.
 37. The compound of claim 1 selected from the groupconsisting of:

Cmpd. R¹ R³ R⁵ R⁶ R⁷ R⁹ 1 D H H H H H 2 H D H H H H 3 H H D H H H 4 H HH D H H 5 H H H H D H 6 H H H H H D 7 D D H H H H 8 D H D H H H 9 D H HD H H 10 D H H H D H 11 D H H H H D 12 H D D H H H 13 H D H D H H 14 H DH H D H 15 H D H H H D 16 H H D D H H 17 H H D H D H 18 H H D H H H 19 HH H D D H 20 H H H D H D 21 H H H H D D 22 D D D H H H 23 D D D D H H 24D D D H D H 25 D D D H H D 26 D D D D D H 27 D D D D H D 28 D D D H D D29 H H H D D D 30 D H H D D D 31 H D H D D D 32 H H D D D D 33 D D H D DD 34 D H D D D D 35 H D D D D D 36 D D D D D D

and pharmaceutically acceptable salts thereof.
 38. The compound of claim1 selected from the group consisting of:

Cmpd. R¹ R³ R⁵ R⁶ R⁷ R⁹ R^(11a) R^(11b) R^(11c) R^(11d) R^(11e) R^(11f)51 H H H H H H D D H H H H 52 H H H H H H H H D D H H 53 H H H H H H H HH H D D 54 H H H H H H D D D D H H 55 H H H H H H D D H H D D 56 H H H HH H H H D D D D 57 H H H H H H D D D D D D 58 D D D H H H D D H H H H 59D D D H H H H H D D H H 60 D D D H H H H H H H D D 61 D D D H H H D D DD H H 62 D D D H H H D D H H D D 63 D D D H H H H H D D D D 64 D D D H HH D D D D D D 65 H H H D D D D D H H H H 66 H H H D D D H H D D H H 67 HH H D D D H H H H D D 68 H H H D D D D D D D H H 69 H H H D D D D D H HD D 70 H H H D D D H H D D D D 71 H H H D D D D D D D D D 72 D D D D D DD D H H H H 73 D D D D D D H H D D H H 74 D D D D D D H H H H D D 75 D DD D D D D D D D H H 76 D D D D D D D D H H D D 77 D D D D D D H H D D DD 78 D D D D D D D D D D D D

and pharmaceutically acceptable salts thereof.
 39. The compound of claim1, wherein the compound is deuterium enriched.
 40. The compound of claim1, wherein the compound is carbon-13 enriched.
 41. The compound of claim1, wherein at least one of the atoms as specified as isotopicallyenriched has isotopic enrichment of no less than about 5%.
 42. Thecompound of claim 1, wherein the compound is a hydrochloride salt.
 43. Apharmaceutical composition comprising a compound of claim 1, or anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomersthereof; or a pharmaceutically acceptable salt thereof; and one or morepharmaceutically acceptable excipients.
 44. The pharmaceuticalcomposition of claim 43, further comprising a second therapeutic agent.45. The pharmaceutical composition of claim 44, wherein thepharmaceutical composition is formulated for single dose administration.46. The pharmaceutical composition of claim 45, wherein thepharmaceutical composition is formulated for single dose administration.47. The pharmaceutical composition of claim 46, wherein the oral dosageform is a tablet or capsule.